Tigecycline in the Treatment of Patients with Necrotizing Skin and Soft Tissue Infections Due to Multiresistant Bacteria

Abstract

Background:

Necrotizing skin and soft tissue infections (NSTI) form a group of aggressive diseases that require radical debridement for infection control. Simultaneously, a high-dose broad spectrum antibiotic regimen needs to be initiated with control of septic complications in the intensive care setting. The aim of this work is to analyze the efficacy and safety of tigecycline in a subpopulation of hospitalized, severely ill surgical NSTI patients who were documented in a large multicenter non-interventional study on tigecycline use in routine clinical practice.

Methods:

A total of 1,025 patients with severe infections including complicated skin and soft-tissue infections (cSSTI, n=163; 15,9%) were enrolled in a prospective multi-center non-interventional study. Patients were to receive an initial intravenous dose of 100 mg tigecycline, followed by 50 mg twice daily. Prospectively documented parameters included clinical findings, APACHE II score, microbiological and standard laboratory assessments, surgical measures, and clinical outcomes including adverse events.

Results:

Of 163 patients were treated for cSSTI, with the largest subgroup being NSTI patients (n=50, 30.7% of all cSSTI, mean age 61 y, median APACHE II score 20). Forty-eight NSTI patients (96%) had at least one comorbidity. In 80% of patients, the treatment was started after previous antibiotic treatment had failed and in 34% resistant pathogens were isolated (28% methicillin resistant Staphyloccocus aureus [MRSA], 4% extended-spectrum-beta-lactamase (ESBL)-producing bacteria, and 2% vancomycin-resistant Enterococci (VRE). Tigecycline was administered as a single agent in 32 patients; 17 received combination regimens. Data from one patient were not reported. Rates of clinical cure or improvement with tigecycline treatment were 90.2%. Two patients (4%) had drug related adverse events (one thrombocytopenia and one fever/chills); 10 patients (20%) died.

Conclusions:

Tigecycline alone or in combination therapy was an effective and safe antibiotic treatment in critically ill and antimicrobially pre-treated patients with NSTI frequently caused by resistant pathogens.

Skin and soft tissue infections (SSTI) belong to the most frequent bacterial infections in human beings. They represent one of the most common indications for antibiotic treatment causing approximately 10% of hospital admissions in the USA, with trends toward increasing rates [1,2]. With a wide spectrum of etiologies, clinical manifestations and severities [3,4], SSTI are the third most common cause of severe sepsis or septic shock [5].

A classification schema proposed by the FDA and frequently used in clinical trials differentiates between uncomplicated and complicated SSTI (cSSTI), where the latter group is characterized by either deep soft tissue involvement, severe patient immuno-suppression or the necessity for major surgical intervention [6]. Among cSSTI, necrotizing soft tissue infections (NSTI) are a rare but unvariably serious subcategory with an incidence of approximately two cases per 100,000 population per year [7].

Successful treatment of necrotizing soft tissue infections is based on early detection, immediate adequate calculated antibiotic treatment and early radical surgical debridement. Patients often require intensive care to manage septic complications [8,9,10].

There is growing evidence for an increasing number of patients suffering from NSTI caused by resistant gram-positive and gram-negative bacteria [11]. Many antibiotic regimens have been used in NSTI, but few studies report on sizeable populations treated with a standardized antibiotic regimen. In recent years, some major pivotal trials on novel antimicrobial agents targeting complicated SSTI have been conducted [12,13,14]. However, the diagnosis of NSTI was an exclusion criterion in most of these studies.

Tigecycline is a glycylcycline antibiotic with a broad antibacterial spectrum covering most pathogens encountered in NSTI, including multiresistent pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing Enterobacteriaceae and vancomycin-resistant Enterococci (VRE).

The intravenous drug is licensed for complicated SSTI and has been successfully used in clinical practice for a number of years. A large prospective non-interventional trial (NIS) was performed to document the efficacy and safety of tigecycline in routine clinical practice and to extend the evidence base in patients with characteristics encountered in the real-world hospital setting [15]. Our present analysis is focused on the treatment results of tigecycline in a subpopulation of patients suffering from NSTI who were documented in this NIS.

Patients and Methods

Study objectives and design

Physicians from 137 participating hospitals in Germany documented the treatment and outcomes of patients receiving tigecycline for severe infections in a multicenter observational, non-interventional prospective study [15].

Safety and efficacy data were recorded during routine clinical patient care. Apart from use of the recommended tigecycline dosage, there were no protocol-defined specifications concerning either the characteristics of patients, type of infection, antibiotic regimen, and other treatments or the diagnostic measures and monitoring.

The study was performed in accordance with applicable national regulatory and institutional standards. The local ethics committee (Ethik-Kommission der Aerzte-kammer Westfalen-Lippe, Muenster, AZ: 2006-221-f-S) approved the observational plan prior to the start of the study that was registered in the ClinicalTrials.gov study database (ClinicalTrials.gov identifier NCT00488488).

Definition of clinical entities

cSSTI were diagnosed according to current standards as previously described for this study [12]. Briefly diagnosis of NSTI was based on clinical assessment by macroscopic appearance of the lesions and criteria described by Kujath et al. [16]. Nosocomial infections were diagnosed after >48 h of hospitalization. Community-acquired infections were diagnosed before that time point. Patients with diabetic foot infections were excluded from the NSTI subpopulation.

Study medication

Tigecycline is licensed for complicated intra-abdominal infections (cIAI) and complicated skin and soft tissue infections (cSSTI) in Europe [17]. The study protocol involved an initial intravenous dose of 100 mg of tigecycline (Tygacil^®; Pfizer Pharma GmbH, Germany), followed by 50 mg tigecycline every 12 h, as recommended in the product label. Treatment duration and concomitant medications including additional antimicrobial agents were at the discretion of the investigators.

Data acquisition and evaluations

Data collected at the baseline visit included patient demographic data, medical history, comorbidities and concomitant treatments, clinical diagnosis and localization of infection, surgical interventions, prior antimicrobial therapy, and measures of disease severity (APACHE II). Infections were classified as hospital- versus community-acquired for infections first appearing in a patient hospitalized for more or less than 48 h.

Concerning antimicrobial therapy, the following data were documented: Tigecycline use including indication, dosage, and duration of therapy, use as monotherapy vs. combination with other antimicrobial agents, use as calculated vs. targeted therapy, use as first-line vs. salvage therapy and switch to other antibiotics agents.

The investigators rated the therapeutic outcome as cure, improvement with no further need of antibiotic treatment, failure to respond, or not evaluable. Rating as cure required full resolution of symptoms of infection, whereas improvement was defined as substantial improvement of symptoms but without complete resolution of infection.

Usual laboratory and microbiological results such as identity of microorganisms and susceptibility data were documented according to local practice. Adverse events were documented and reported as required by German authorities and legislation.

Study data were recorded prospectively by the attending physicians (i.e., investigators) on case report forms. Patient-related data were anonymized, processed and used according to German data privacy regulations.

Definition of adverse events

An adverse event (AE) was defined as any unexpected medical occurrence irrespective of a causal relation to tigecycline. The definition also included clinically relevant deterioration of a pre-existing condition, absence of an expected drug reaction and AEs occurring from overdose, abuse, or withdrawal of the study drug. Unclear events in terms of that definition were to be handled as adverse events. Drug-related AEs were those suspected to have a potential causal relation to tigecycline by the investigator.

A serious AE (SAE) was defined as any unexpected medical occurrence that was life-threatening or resulted in death, (prolonged) hospitalization or persistent/substantial disability/incapacity, malignant disease, congenital anomaly/birth defect, or was categorized as an important medical event (an event considered serious because it may have jeopardized the subject and may required intervention to prevent another serious condition as listed before. This included lack of effectiveness of tigecycline within the expected spectrum of activity).

Statistical analysis

This final analysis included all completed case report forms entered in the electronic study database. The SAS^® 8.2 software package (SAS Institute Inc., Cary, North Carolina) was used for descriptive statistical analyses. Continuous variables were reported as median (range) or mean (±standard deviation), categorical variables as number of patients (percentage).

Results

Patient demographic and clinical characteristics

Among the 1025 patients who were treated with tigecycline in 137 participating hospitals, 163 had cSSTI. Of these patients, 50 had NSTI. Demographic and clinical characteristics of evaluable NSTI patients are presented in Table 1.

Table 1.

Patient Characteristics at Baseline

Demographic characteristics	n=50
Male gender, % (n)	52.0% (26 )
Mean age, years +/− SD (range)	61.3 (21–89)
Clinical parameters
Mean body weight, kg +/− SD (range)	87.0 +/− 16.8 (55–123)
APACHE II Score >20, % (n)	44.4% (22 )
Mean APACHE II Score +/− SD (range)	18.4 +/− 7.4 ( 5–35)
Patient on intensive care unit at the time of treatment initiation, % (n)	38.0% (19 )
Comorbidities, % (n) (in ≥10% of patients)
At least 1 comorbidity	94.0% (47 )
Hypertension	66.0% (47 )
Arteriosclerosis/coronary heart disease	42.0% (21 )
Cardiac insufficiency	34.0% (17 )
Myocardial infarction, previous	12.0% ( 6 )
Stroke, previous	10.0% ( 5 )
Diabetes mellitus	46.0% (23 )
Renal impairment	38.0% (19 )
Chronic obstructive lung disease	30.0% (15 )
Smoking	22.0% (11 )
Obesity	16.0% (13 )
Solid organ tumor	14.0% ( 7 )
Alcohol abuse	10.0% ( 5 )
Chronic liver disease	10.0% ( 5 )
Comedications other than anti-infectives, n (%)
Any medication	96.0% (48 )
Anti-coagulants	84.0% (42 )
Cardiovascular medications	78.0% (39 )
Drugs affecting metabolic functions, hormones	44.0% (22 )
Respiratory medications	42.0% (21 )
Immunosuppressants	6.0% ( 3 )
Cytotoxic drugs	4.0% ( 2 )

APACHE II=Acute Physiology and Chronic Health Evaluation II; SD=standard deviation.

A large proportion of this NSTI subpopulation with a median age of 66 y was treated in intensive care units (38%). The median APACHE II score was 20, with 25% of the patients having scores of ≥23.

Virtually all patients had at least one comorbidity, mostly cardiovascular diseases (>66%), diabetes mellitus (46%), renal impairment (38%), and chronic obstructive pulmonary disease (30%). Non-anti-infective comedications at baseline included anticoagulants (84%), drugs acting on metabolic functions (78%), and respiratory medications (42%).

Types and sites of infection

The majority of NSTIs affected the lower extremities (56%) and trunk (26%), and others were localized at upper extremities (8%), perineum/genitals (8%), or head and neck (6%). The infections involved deep tissue layers in 86% of patients. Most of the NSTI were acquired in the hospital (60%). In addition to the necrotizing infection, some patients had abscesses (6%), and gangrene associated with vascular occlusive disease (4%).

Microbiological findings prior to tigecycline therapy

Bacterial pathogens were isolated in 40 patients (80%) (Table 2). Staphylococcus aureus was the most frequently isolated species (44%), followed by Escherichia coli (24%) and Enterococci (22%). Multidrug-resistant pathogens were identified in 34% of patients including methicillin-resistant S. aureus (MRSA; 28%), ESBL producers (4%) and vancomycin-resistant Enterococcus (2%).

Table 2.

Pathogens Isolated before Tigecycline Therapy

Patients with available pathogen isolates, % (n)	80.0% (40)
Gram-positive bacteria	68.0% (34)
Staphylococcus aureus	44.0% (22)
Enterococcus spp.	22.0% (11)
Streptococcus spp.	2.0% (1)
Gram-negative bacteria	36.0% (18)
Enterobacteriaceae	30.0% (15)
Escherichia coli	24.0% (12)
Klebsiella spp.	2.0% (1)
Nonfermenters (other than P. aeruginosa)	2.0% (1)
Pseudomonas aeruginosa	4.0% (2)
Multiresistant pathogens	34.0% (17)
MRSA	28.0% (14)
VRE	2.0% (1)
ESBL producers	4.0% (2)
Other pathogens (not further specified)	8.0% (4)

MRSA=methicillin-resistant S. aureus; VRE=vancomycin-resistant Enterococcus; ESBL=extended-spectrum beta-lactamase.

Among the tested bacterial isolates 94% (30 of 32) were susceptible to tigecycline. Exceptions included one Pseudomonas aeruginosa and one enterobacterial isolate.

Treatment of NSTI

Prior therapy

Eighty percent of the patients had received (mostly intravenous) prior antibiotic therapy (Table 3), e.g., mostly fluoroquinolones (26%), cephalosporins (26%), carbapenems (14%), penicillins (12%), and glycopeptides (10%).

Table 3.

Previous Therapy of NSTI

Previous antibiotic therapy, n (%) (in ≥4% of patients)	n=50
Any antibiotics, % (n)	80.0% (40 )
Cephalosporins	26.0% (13 )
Carbapenems	14.0% (7 )
Fluoroquinolones	26.0% (13 )
Penicillins	16.0% (8 )
Glycopeptides	10.0% (5 )
Lincosamides	8.0% (4 )
Mean duration of previous antibiotic therapy, days +/− SD (range)	7.4 +/− 5.3 (1–31)
Surgical therapy prior to tigecyline, % (n)	n=50
Any surgical procedure	78.0% (39 )
Debridement / abscess drainage	48.0% (24 )
Major amputation	8.0% (4 )
Minor amputation	2.0% (1 )
Excision / suture	2.0% (1 )
Other surgical procedures	22.0% (11 )

SD=standard deviation.

A majority of patients had been treated surgically (78%), mostly by necrosectomy (56%), debridement and abscess incision (48%), and amputations (10%). Sanitation of the infectious focus was achieved in 38% of the total NSTI subgroup.

Dosage and modalities of tigecycline therapy

The majority of patients (n=44) received tigecyline at the recommended dosage (a 100 mg initial dose followed by 50 mg given twice daily). Three patients received other dosages; the regimen was not fully reported in three patients (Table 4).

Table 4.

Tigecycline Therapy

Dosage and duration of tigecycline therapy, % (n)	n=50
Initial dosage 100 mg^*	98.0% (49 )
Maintenance dosage 50 mg twice daily^**	88.0% (44 )
Mean treatment duration, days +/− SD (range)	12.6 +/− 7.6 (3–47)
Anti-infective drugs used in combination with tigecycline, n (%)	N=50
Carbapenem	16.0% (8 )
Cephalosporin	8.0% (4 )
Fluoroquinolone	6.0% (3 )
Nitroimidazole	6.0% (3 )
Triazole anti-fungal	4.0% (2 )
Tigecycline treatment mode, % (n)	N=50
First-line therapy	20.0% (10 )
Salvage therapy	80.0% (40 )
Monotherapy	64.0% (32 )
Combination therapy	34.0% (17 )

Other initial dosage: 50 mg

Other maintenance dosages: 50 mg once daily: two patients; 100 mg once daily: one patient; unknown: three patients.

SD=standard deviation.

Tigecycline was used as first-line antibiotic therapy in 20% of the patients, 80% received tigecycline as salvage therapy. In 64% of the patients, tigecycline was given as monotherapy, whereas 34% received antibiotic combination regimens involving a carbapenem, cephalosporin, fluoroquinolone or imidazole derivative in addition to tigecyline. Data from one patient were not reported. The mean duration of tigecycline therapy was 12.6 d (range 3–47 d).

Clinical efficacy

The clinical outcome of tigecycline treatment is shown in Table 5. Treatment outcomes were evaluable in 41 patients. Of these, 90.2% had a successful outcome, defined as cure (51.2%) or improvement without the need of further antibiotic therapy (39.0%). No outcome data were reported for nine of the 50 NSTI patients.

Table 5.

Treatment Outcomes at the End of Tigecycline Therapy According to Risk Factors and Treatment Modalities

Success at end of therapy, % (n) (cure or improvement without the need of further antibiotic therapy)
Total evaluable population (n=41)	90.2% (37)
Risk factor subgroups
Nosocomial infection (n=25)	92.0% (23)
Community-acquired infection (n=4)	100% (4)
APACHE II score ≤20 (n=22)	90.9% (20)
APACHE II score >20 (n=19)	87.5% (14)
Multi-drug resistant pathogens (MRSA, VRE, ESBL producers) (n=12)	100% (10)
Treatment modality subgroups
First-line therapy (n=9)	100% (9)
Salvage therapy (n=32)	87.5 (28)
Monotherapy (n=28)	100% (28)
Combination therapy (n=13)	87.5% (9)

MRSA=methicillin-resistant S. aureus; VRE=vancomycin-resistant Enterococcus; ESBL=extended-spectrum beta-lactamase; APACHE II=Acute Physiology and Chronic Health Evaluation II.

All 28 evaluable patients who received tigecycline monotherapy (100%) were successfully treated. Combination therapy was successful in nine of 12 patients (75.0%). First-line tigecycline therapy resulted in successful outcomes in all nine patients (100%), compared with 87.5% of the 27 pre-treated patients.

All 12 patients who were infected with multiresistant pathogens (100%) had successful outcomes. Patients with APACHE II scores >20 (n=16) had a similar success rate (87.5%) as those with lower scores (90.9%; n=22).

Adverse events

Adverse events were reported in 15 patients. Two of these patients had events classified to be related to tigecycline by the treating physician, including one case of thrombocytopenia and one patient with fever/chills. The latter of these treatment-related events was the only one that resulted in tigecycline discontinuation.

In 11 patients, serious adverse events were reported, including multi-organ failure (five), sepsis (three), and cardiac failure (three). None of the serious adverse events were categorized as associated with tigecycline.

Deaths during study

Ten patients died during follow-up in this study. All of the deceased patients with available APACHE II scores had values of 20 or greater before initiation of tigecycline. All had substantial pre-existing comorbidities, were treated on ICU and received tigecycline as a salvage treatment. Table 6 provides a detailed overview of the deceased patients.

Table 6.

Characteristics of Patients Who Died during Follow-up in the Study

Patient no.	Gender	Age, years	Comorbidities	APACHE II score	ICU yes/no	Salvage therapy yes/no	Cause of death	Outcome assessment at end of therapy
1	m	37	Liver cirrhosis, alcohol abuse, drug abuse, smoker, ischemic stroke	20	Yes	Yes	Liver failure 3 d after end of therapy	Not evaluable
2	m	62	Hypertension, coronary heart disease, cardiac insufficiency, renal failure	23	Yes	Yes	Multi-organ failure after long-term ICU stay	Not evaluable
3	m	50	Iatrogenic immuno-suppression, solid tumor	22	Yes	Yes	Septic shock	Failure
4	f	53	Terminal renal failure	26	Yes	Yes	(Infection was cured) Cardiac arrest 3 d after end of therapy	Success
5	f	85	Hypertension, chronic obstructive pulmonary disease	Not reported	Yes	Yes	Hemorrhagic shock after insertion of chest tube	Not evaluable
6	f	74	Myocardial infarction, coronary heart disease, cardiac insufficiency, arterial occlusive disease, renal failure, chronic obstructive pulmonary disease	21	Yes	Yes	Persistent sepsis	Failure
7	f	53	Hypertension, coronary artery disease, arterial occlusive disease	20	Yes	Yes	Multiple vascular occlusions with multi-organ failure	Not evaluable
8	f	75	Hypertension, cardiac insufficiency, diabetes mellitus, renal failure, obesity, tumor of descending colon	26	Yes	Yes	Cardiac arrest, considered unrelated to study drug	Not evaluable
9	m	70	Hypertension, coronary heart disease, cardiac insufficiency, myocardial infarction, renal failure	28	Yes	Yes	(Infection was cured) Multi-organ failure 44 d after end of therapy	Success
10	m	58	Renal failure, obesity, iatrogenic immuno-suppression, acute myeloid leukemia	35	Yes	Yes	De-escalation of treatment due to multi-organ failure and poor prognosis	Not evaluable

APACHE II=Acute Physiology and Chronic Health Evaluation II; ICU=intensive care unit.

Discussion

To the best of our knowledge, this is the largest documented cohort of patients with NSTI treated using fairly homogeneous antibiotic regimens, with tigecyline applied as monotherapy in the majority of patients. The NSTI population evaluated in this analysis included a large proportion of elderly patients, with multiple relevant comorbidities, high rates of deep tissue involvement, nosocomial infection, high APACHE II scores and failure of previous antibiotic therapy. Despite the prevalence of adverse factors listed above, tigecyline reached high success rates in all analyzed subgroups. The high clinical success rate in the evaluable population of 90.2% indicates that tigecycline used as single agent or in combination therapy is an appropriate option for this critically ill population of NSTI patients.

Current guidelines recommend the initiation of therapy with broad-spectrum antimicrobials within 1 h after the diagnosis of severe sepsis or septic shock [18]. This recommendation is based on the evidence that delaying antimicrobial therapy in patients with sepsis-related hypotension is associated with increased mortality [19]. Whether the initial empirical antimicrobial treatment in NSTI should cover resistant pathogens remains to be decided individually, based on the local epidemiology and the individual risk profile of the patient. Our data suggest that there is at least an increasing risk for involvement of resistant bacteria in patients with NSTI. Tigecycline, with its broad spectrum that includes multi-resistant gram-positive and gram-negative bacteria, has shown good clinical activity in this critically ill population.

Radical surgical debridement is essential for survival in NSTI [1,4]. Early surgery (within 12 h after admission) has been shown to improve survival substantially [20]. Re-debridement is also a necessary step in the surgical care of NSTI patients. Nevertheless, in a recently published large cohort the number of debridements per patient decreased substantially over a 10-year period [21]. In our NSTI cohort, 78% of the patients surgical measures have been performed on treatment with tigecycline, of which debridement was the most frequent one (48%). Amputation can be avoided by initial radical debridement. The relatively high amputation rate in our NSTI patients (10%) indicates that initial surgical source control was incomplete in a considerable percentage of patients when tigecycline therapy was started.

Few of the reported adverse events were considered causally related to tigecycline, and none of these was a serious adverse event. The number of deaths observed in this analysis was consistent with the severity of the condition, and remained below the mortality expected at a median APACHE II score of 20.

Limitations of this study include the observational study design that may be associated with several biases. However, the low overall incidence of NSTI precludes prospective comparative trials in this indication. Criteria used for diagnosis and treatment success evaluation were not standardized (e.g., no photographic documentation was performed).

Conclusion

In this analysis of a large, highly comorbid group of patients with necrotizing soft tissue infections from a non-interventional multi-center study, tigecycline was associated with high treatment success rates in the full analysis set as well as in subgroups with different treatment modalities and risk factors, including high APACHE II scores and infection with multi-drug resistant pathogens. These results add to the accumulating evidence that supports the use of tigecycline in difficult-to-treat complicated soft tissue infections that require broad pathogen coverage and effective tissue penetration.

Footnotes

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.

Author Disclosure Statement

Dr. Eckmann has received payment from the following companies: Pfizer, Bayer Health Care, Novartis, Astra Zeneca, and Durata.

Dr. Heizmann has received payments from Bayer and Pfizer.

Dr. Bodmann has received payments from Bayer, Pfizer, Astellas, Infektopharm, MSD, and AstraZeneca.

This study was supported by Wyeth Pharma AG, Muenster, Germany, (now Pfizer Pharma GmbH, Berlin).

Drs. Eckmann, Heizmann, and Bodmann were clinical investigators for Wyeth Pharma GmbH (now Pfizer Pharma GmbH). Drs. von Eiff, Petrik, and Loeschmann are employees of Pfizer Pharma GmbH.

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