Medicine and Interdisciplinary Emergency Medicine, Eberswalde, Germany

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1 J Antimicrob Chemother 2013; 68 Suppl 2: ii15 ii24 doi: /jac/dkt141 Efficacy of tigecycline for the treatment of complicated skin and soft-tissue infections in real-life clinical practice from five European observational studies Philippe Montravers 1 *, Matteo Bassetti 2, Hervé Dupont 3, Christian Eckmann 4, Wolfgang R. Heizmann 5, Xavier Guirao 6,7, Miguel Sánchez García 8, Maria Rita Capparella 9, Damien Simoneau 9 and Klaus Friedrich Bodmann 10 1 Univ Paris Diderot, Sorbonne Paris Cité and APHP, Centre Hospitalier Universitaire Bichat-Claude Bernard, Département d Anesthésie Réanimation, Paris, France; 2 Clinica Malattie Infettive, AOU Santa Maria della Misericordia, Udine, Italy; 3 University Jules Verne of Picardy, North Hospital of Amiens, Amiens, France; 4 Klinikum Peine, Department of General, Visceral and Thoracic Surgery, Peine, Germany; 5 Center for Microbiology and Infectious Diseases, Berlin, Germany; 6 Hospital General de Granollers, Granollers, Spain; 7 Universitat Internacional de Cataluña (UIC), Barcelona, Spain; 8 Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain; 9 Pfizer International Operations, Paris, France; 10 Klinikum Barnim GmbH, Werner Forssmann Hospital, Clinic for Internal Intensive Medicine and Interdisciplinary Emergency Medicine, Eberswalde, Germany *Corresponding author. Department of Anaesthesiology and Surgical Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, CHU Bichat, 46 Rue Henri-Huchard, Paris 75018, France. Tel: ; Fax: ; philippe.montravers@bch.aphp.fr Objectives: Tigecycline is an approved treatment for complicated skin and soft-tissue infections (csstis). The efficacy of tigecycline as monotherapy or in combination with other antibacterials in the treatment of cssti in routine practice is described. Patients and methods: Individual patient-level data were pooled from five European observational studies (July 2006 to October 2011). Results: A total of 254 cssti patients who received tigecycline were included (mean age years). Of these, 34.4% were in intensive care units, 54.5% acquired their infection in hospital and 90.9% had at least one comorbidity. Infection most commonly affected the limbs (62.4%) and 43.8% of infections were classified as necrotizing. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores at the beginning of treatment were (n¼205) and (n¼32), respectively, indicating high disease severity. Staphylococcus aureus (52.7%), Escherichia coli (18.0%) and Enterococcus faecium (12.0%) were the most frequently isolated pathogens; 32.9% of infections were polymicrobial and 30.5% were due to resistant pathogens. Overall, 71.8% received tigecycline as monotherapy and 28.2% as combination therapy for a mean duration of 12 days. Clinical response rates at the end of treatment were 79.6% for all patients who received the standard dosage (183/230), 86.7% for patients who received tigecycline as monotherapy (143/165), 75.0% for patients with a nosocomial infection (96/128), 75.3% for patients with an APACHE II score.15 (61/81) and 58.3% for patients with a SOFA score 7 (7/12). Conclusions: In these real-life studies, tigecycline, alone and in combination, achieved favourable clinical response rates in patients with cssti with a high severity of illness. Keywords: broad-spectrum antibacterial therapy, necrotizing skin infections, non-interventional studies, glycylcycline antibiotics Introduction Complicated skin and soft-tissue infections (csstis) encompass a heterogeneous group that affects the deep soft tissue. They can include infections that require significant surgical intervention, such as ulcers, burns and major abscesses, or be related to a significant underlying disease state, such as neutropenia or tissue necrosis, which complicates the response to treatment. 1 3 Although the predominant bacteria associated with skin and softtissue infections in hospitalized patients include Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus spp., 4 many csstis, especially those in patients previously treated with antibiotics, are likely to be polymicrobial and require broad-spectrum antibiotic treatment. 1,5 Furthermore, increasing # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oup.com ii15

2 Montravers et al. resistance among both Gram-positive and Gram-negative bacteria causing both hospital- and community-acquired cssti makes empirical treatment decisions difficult, and the number of currently available appropriate antimicrobial agents is limited. 6 Failure to initiate appropriate antimicrobial therapy early in the course of treatment can lead to an increased risk of clinical failure and increased healthcare costs. 7 There is an increasing need for effective antibiotics in the population of critically ill patients at high risk of infection with multidrug-resistant pathogens. Tigecycline, a broad-spectrum glycylcycline antibiotic, is approved in the USA and Europe for the treatment of patients with csstis and complicated intra-abdominal infections (ciais). In vitro studies have shown that tigecycline has good activity against multiple skin pathogens, including some antibioticresistant strains. 6,8 10 Tigecycline has a large volume of distribution and achieves high concentrations in tissues and low concentrations in serum. 5,11 A recent study examining the penetration of tigecycline into skin and soft tissue in patients with csstis showed that concentrations of tigecycline were higher in skin and soft tissue than in serum at each of three time intervals, 2 4, 5 7 and 8 10 h, with mean tissue:serum ratios of 3.8 (range ), 5.2 (range ) and 2.8 (range ), respectively. 12 The efficacy of tigecycline versus other antimicrobials for the treatment of cssti has been demonstrated in two double-blind, Phase III randomized clinical trials (RCTs). 13,14 In a pooled analysis of these trials, tigecycline monotherapy was as effective for the treatment of cssti as a standard combination regimen of vancomycin and aztreonam. 15 In September 2010, the US FDA issued a warning regarding an imbalance in overall mortality in patients treated with tigecycline that was noted in the completed clinical trials. 16 A number of meta-analyses have also noted numerically higher all-cause mortality in patients treated with tigecycline versus comparators in RCTs The European Medicines Agency reviewed the evidence and concluded that the benefits of tigecycline continue to outweigh its risks; however, they issued a recommendation that tigecycline should be used only when it is known or suspected that other antibiotics are not suitable. 21 The RCTs conducted to date and included in the metaanalyses have included only a small number of intensive care unit (ICU) or critically ill patients. Patients with the more severe deep infections were excluded from the two tigecycline Phase III trials in cssti and few were very ill at baseline. 15 In real-life clinical practice, tigecycline represents an option for the treatment of patients with complicated infections for which other antibiotics may not be suitable. 11 Many of these patients are critically ill in an ICU or surgical ward, and have substantial comorbidities and higher disease severity than those treated with tigecycline in the published trials. Further data are needed to clarify the role of tigecycline in the treatment of critically ill patients with cssti. The objective of this analysis was to evaluate the clinical efficacy of tigecycline in patients with cssti treated in the routine hospital care setting in five non-interventional, observational studies conducted in four European countries [Germany, Italy, France and two studies in Spain (Spain-1 and Spain-2)]. The demographic characteristics and comorbidities of patients with cssti and the prescription of tigecycline and concomitant use of other antibiotics were also evaluated. Patients and methods This analysis included data collected by hospital-based physicians on the treatment and outcomes of patients receiving tigecycline in five noninterventional, observational studies conducted in Europe from July 2006 to October The study from Germany has been published in full, 22,23 and preliminary data from three of the studies (Italy, France and Spain-2) have been presented or published previously The design of each study and the methodology of data acquisition, assessment of clinical efficacy and the statistical analysis of the five observational studies is described in the accompanying article by Bassetti et al. 27 In brief, due to the observational nature of the studies, there were few protocol specifications or inclusion/exclusion criteria. Hospitalized patients were included if they received tigecycline for any indication during the study period. Spain-1 included only patients with a diagnosis of cssti or ciai. Two studies (France and Spain-2) included only patients admitted to the ICU. The administration of tigecycline, dosage, duration of treatment and prescription of other antibiotics during or after the start of tigecycline was at the discretion of the physician. All concomitant medications were permitted. The standard approved dosage of tigecycline is an initial loading dose of 100 mg, followed by 50 mg intravenously every 12 h (twice daily), as recommended in the summary of product characteristics. 11 This research was conducted in accordance with the Declaration of Helsinki and all national and institutional standards. The protocol of each study was approved by the local ethics committee or institutional review board. Due to the non-interventional, observational nature of the studies, written informed consent was not required for enrolment in the studies in Germany, Italy and Spain-2. Written informed consent was obtained from patients prior to participation in the studies from France and Spain-1. Definition of cssti The diagnosis of cssti was at the discretion of the physician. Skin and soft-tissue infections are commonly defined as complicated when surgical intervention is required and/or the infectious process is suspected or confirmed to involve deeper soft tissue such as the fascia and/or muscle layers. Infection may also be considered complicated when it occurs in an immunocompromised host or in the setting of a complicating condition such as diabetes mellitus, peripheral vascular disease or peripheral neuropathy. 2,3 In addition to the infection, the patient may have at least two of the following signs and symptoms: drainage or discharge, fever, erythema, swelling, localized warmth, pain and/or white blood cell count of cells/mm 3. Data acquisition and evaluations Data were collected on case report forms at the start of therapy with tigecycline and included patients characteristics, infection diagnosis, disease severity score, surgical intervention prior to tigecycline use, microbiologically isolated pathogens and therapy regimens. The severity of disease at the start of tigecycline therapy was evaluated by the Acute Physiology and Chronic Health Evaluation (APACHE) II score in Germany, Italy, Spain-1 and Spain-2 and by the Sequential Organ Failure Assessment (SOFA) score in France and Spain-2. Reasons for tigecycline use were pre-specified in the case report form with check boxes. Local hospital laboratory and microbiology techniques were used to identify isolated pathogens at baseline in four studies (Germany, Spain-1, France and Spain-2). 28 The pathogenic species (or species groups) to be documented were pre-specified in the case report form with check boxes. Clinical outcome Clinical outcome was assessed by the investigator at the end of treatment (EOT) or upon discharge. For this analysis, patients who were ii16

3 Efficacy of tigecycline for complicated skin and soft-tissue infections in Europe JAC assessed by the investigator as cured or improved, with no further antibiotic required were assigned an outcome of response and patients who were assessed by the investigator as failure or improved, with further antibiotic required were assigned an outcome of non-response. Patients whose outcome could not be assessed for any reason were assigned an outcome of indeterminate. Patients who died following a successful response to tigecycline at EOT were counted as responders and patients who died before or at EOT were counted as non-responders. Safety The numbers of adverse events (AEs), serious AEs (SAEs), premature discontinuations and all-cause deaths occurring at any time during the study, including the follow-up period, were recorded. Mortality rates were examined by disease severity score at the time of tigecycline administration. A detailed description of the criteria for the assessment of safety is provided in the accompanying article by Guirao et al. 29 Statistical analysis Descriptive statistics included relative frequencies for categorical variables and means (and standard deviations) or medians (and IQRs) for continuous variables. A pooled analysis of patient-level data in the five studies was conducted for selected characteristics. 27 Only patients with a single diagnosis of cssti were included; patients who were diagnosed with cssti plus another infection (e.g. both cssti and ciai) were excluded. Data were analysed in tabulated summaries with the number of patients with available (i.e. non-missing) data as the denominator. Clinical response rates were calculated for patients who received the standard dose of tigecycline as recommended in the summary of product characteristics, 11 and were stratified according to mean APACHE II ( 15 or.15) and SOFA (,7 or 7) scores documented at baseline, mode of infection acquirement (nosocomial or communityacquired) and treatment with tigecycline as monotherapy or in combination therapy, and as first-line or second-line therapy. Results Patient characteristics Across the five observational studies, tigecycline was used to treat 254 patients with cssti, representing 14.3% of all patients. Patient demographics, disease severity scores at baseline, mode of infection acquirement and comorbidities are shown in Table 1. Of the total pooled cssti patients, 61.8% were male, with a mean age of 63.2 years and mean body mass index (BMI) of 28.1 kg/m 2 ; 51.6% of patients were over the age of 65 years. The majority (72.7%) of patients had a history of prior antibacterial therapy. Two hundred and thirty-one (90.9%) patients had at least one comorbidity, including renal insufficiency (44.2%), diabetes mellitus (54.5%), arteriosclerosis/coronary heart disease (50.6%) and hypertension (78.0%); 27.3% of patients were classified as obese. The distribution of patients with nosocomial (54.5%) and community-acquired (45.5%) infection varied across the studies, with the highest percentage of nosocomial infections found in Spain-2 and Italy. There was heterogeneity between the studies with regard to the percentage of patients enrolled from the ICU, with all patients (100.0%) in the studies from France and Spain-2 in the ICU compared with 5.6% of patients in the study from Spain-1, 29.4% from Germany and 17.1% from Italy (Table 1). Disease severity scores APACHE II scores were collected for 205 patients in four studies (Germany, Italy, Spain-1 and Spain-2). Mean APACHE II scores in these countries ranged from 5.0 to 17.6, with the highest mean score recorded for patients in Spain-2 (Table 1). Overall, 44.4% of patients had an APACHE II score.15 and the mean score among these patients was 22.6 (median 21.0). SOFA scores were collected for 32 patients in France and Spain-2. Mean SOFA scores in these countries were 5.7 and 6.0, respectively. Overall, 40.6% of patients had a SOFA score 7 and the mean score among these patients was 9.8 (median 11.0). Figure 1 shows the percentage of patients across the five studies with high disease severity at the time of tigecycline administration, as evidenced by APACHE II score.15 or SOFA score 7. Description of cssti A description of infection characteristics was available for 198 patients in three studies (Germany, Spain-1 and France) (Table 2). The majority of csstis across these studies involved penetration to the deep soft tissue (75.5%). Necrotizing infection (43.8%) was the most common type of cssti. An infected wound or surgical site was responsible for 41.2% of csstis in Spain-1, and abscess was observed in 20.8% of infections overall (Table 2). Most infections documented affected the limbs (62.4%), and the overall majority of patients required surgical intervention for their condition (69.0%). Antibiotic treatment Across the five studies, there were 230 cssti patients (90.6%) who received the standard dose of tigecycline, with a mean duration of therapy of days (range 1 50) (Table 3). Tigecycline was administered first-line to 44.4% of patients for whom these data were available, and 71.8% were given tigecycline as monotherapy (Table 3). There was heterogeneity across the studies in the use of tigecycline as combination therapy to treat cssti, with the highest rate recorded in Spain-2 (73.3%) and the lowest in Italy (4.9%). Data on the concomitant use of antibacterials were available for 69 patients in Germany, Spain-1, France and Spain-2 (Table 4). Although there were differences in prescribing practices between countries, the most common classes of antibiotics given in combination with tigecycline were third- and fourthgeneration cephalosporins in Germany (35.7%), fluoroquinolones in France (44.4%) and aminoglycosides in France (33.3%), Spain-1 (28.6%) and Spain-2 (27.3%) (Table 4). Reasons for tigecycline use Data on the main reasons for tigecycline use were available for 254 patients (Table 5). The most common reasons given for tigecycline use in patients with cssti were failure of previous therapy and broad-spectrum coverage (given in 44.1% and 48.8% of patients, respectively). Tigecycline was also administered when there was a suspicion of resistant pathogens (39.8% of patients). Renal failure was listed as a reason for 12.5% of patients. ii17

4 Montravers et al. Table 1. Summary of patient characteristics Germany Italy Spain-1 France Spain-2 Number of cssti patients Demographics male, n (%) 97 (59.5) 20 (48.8) 13 (72.2) 15 (88.2) 12 (80.0) 157 (61.8) age (years), mean+sd (range) (19 89) (24 90) (44 88) (40 75) (25 75) (19 90) BMI (kg/m 2 ), mean+sd NA NA Clinical characteristics, n (%) ICU admission 48 (29.4) 7 (17.1) 1 (5.6) 17 (100.0) 14 (100.0) a 87 a (34.4) history of prior antibacterial 117 (72.2) a 30 (73.2) 6 (33.3) 16 (94.1) 15 (100.0) 184 a (72.7) presence of 1 comorbidity 157 (96.3) 38 (92.7) 17 (94.4) 7 (41.2) 12 (80.0) 231 (90.9) Mode of infection acquirement nosocomial, n (%) 65 (40.1) 34 (82.9) 14 (77.8) 12 (70.6) 13 (86.7) 138 (54.5) community, n (%) 97 (59.9) 7 (17.1) 4 (22.2) 5 (29.4) 2 (13.3) 115 (45.5) missing/unknown, n Severity/organ dysfunction scores APACHE II score, n NA mean+sd (range) (0 35) (4 19) (0 13) (7 31) (0 35) 15, n (%) 65 (44.5) 39 (95.1) 4 (100.0) 6 (42.9) 114 (55.6) 15, mean (median) 8.4 (8.0) 9.8 (9.0) 5.0 (3.5) 10.3 (10.5) 8.9 (9.0).15, n (%) 81 (55.5) 2 (4.9) 0 (0) 8 (57.1) 91 (44.4).15, mean (median) 22.6 (22.0) 18.5 (18.5) 23.0 (22.5) 22.6 (21.0) missing/unknown, n SOFA score, n NA NA NA mean+sd (range) (0 13) (0 11) (0 13),7, n (%) 10 (58.8) 9 (60.0) 19 (59.4),7, mean (median) 2.8 (2.5) 3.4 (3.0) 3.1 (3.0) 7, n (%) 7 (41.2) 6 (40.0) 13 (40.6) 7, mean (median) 9.9 (10.0) 9.8 (11.0) 9.8 (11.0) Patients with 1 comorbidity, n comorbid conditions, n (%) b hypertension 128 (81.5) NA 10 (58.8) NA 7 (58.3) 145 (78.0) diabetes mellitus 92 (58.6) 21 (55.3) 5 (29.4) 4 (57.1) 4 (33.3) 126 (54.5) arteriosclerosis/chd 88 (56.1) NA 0 NA NA 88 (50.6) heart failure 69 (43.9) 17 (44.7) 1 (5.9) NA 2 (16.7) 89 (39.7) COPD 40 (25.5) 11 (28.9) 2 (11.8) NA 5 (41.7) 58 (25.9) renal insufficiency 84 (53.5) 15 (39.5) 2 (11.8) 0 1 (8.3) 102 (44.2) hepatic failure 13 (8.3) 4 (10.5) (16.7) 19 (8.2) neoplasia 16 (10.2) 8 (21.1) NA NA 2 (16.7) 26 (12.6) immunosuppression 9 (5.7) 5 (13.2) 2 (11.8) 4 (57.1) c 2 (16.7) 22 (9.5) obesity 47 (29.9) 7 (18.4) d 4 (23.5) 5 (71.4) 0 d 63 (27.3) d alcohol abuse 15 (9.6) 3 (7.9) 2 (11.8) NA 1 (8.3) 21 (9.4) smoking 33 (21.0) NA 7 (41.2) NA 1 (8.3) 41 (22.0) CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; NA, not available. Percentages were calculated for patients with non-missing data only. a Data were missing for one patient. b Percentages of comorbid conditions were calculated for patients with at least one comorbidity. c Includes neoplasia in France. d Includes study-level data from Italy and Spain-2. ii18

5 Efficacy of tigecycline for complicated skin and soft-tissue infections in Europe JAC Pathogens isolated at baseline Microbiological data at baseline were collected for 213 patients in Germany, Spain-1, France and Spain-2. More than one pathogen was isolated from 70 (32.9%) patients, with 167 (78.4%) having at least one pathogen. Among patients with at least one isolate, S. aureus was the most frequent Gram-positive Patients with APACHE II score >15 or SOFA score 7 (%) Germany (n = 146) 4.9 Italy (n = 41) 0 Spain-1 (n = 4) 41.2 France (n = 17) 57.1 Spain-2 (n = 14) Figure 1. Disease severity at baseline in patients with cssti. Percentages were calculated for patients with non-missing data only. Disease severity was assessed by APACHE II score in Germany, Italy, Spain-1 and Spain-2, and by SOFA score in France. bacterium, occurring in 88/167 (52.7%) of the samples. E. coli was the most common Gram-negative bacterium, identified in 30/167 (18.0%). Other pathogens isolated in.5% of patients for whom microbiological data were available included Enterococcus spp. (15.2%), specifically Enterococcus faecium (12.0%) and Enterococcus faecalis (10.2%). Acinetobacter baumannii was isolated in five (38.5%) patients in Spain-2 and P. aeruginosa was identified in five (3.7%) patients in Germany and three (23.1%) patients in Spain-2. A pooled analysis of the proportion of patients with selected resistant pathogens [including extendedspectrum b-lactamase (ESBL)-producing E. coli, vancomycinresistant Enterococcus (VRE) and methicillin-resistant S. aureus (MRSA)] showed that, overall, 65/213 (30.5%) patients had at least one resistant pathogen at baseline, and of these 56 (86.2%) were MRSA. Further data on the microbiological findings from these studies are provided by Heizmann et al. 28 Clinical outcome Clinical response rates for cssti patients who received the standard dose of tigecycline are shown in Table 6 and Figures 2 4. Overall, 79.6% (183/230) of patients who received treatment with tigecycline alone or in combination showed clinical cure or improvement without the need for additional antibiotics (Figure 2). Clinical response rates ranged from 62.5% in France (where all of the patients were in the ICU) to 93.8% in Spain-1 (where only one patient was in the ICU). When patients were Table 2. Description of csstis Germany Italy Spain-1 France Spain-2 Number of patients 163 NA NA 198 Infection subtype a abscess, n (%) 35 (21.7) 2 (11.8) NA 37 (20.8) cellulitis, n (%) 7 (4.3) 3 (17.6) NA 10 (5.6) necrotizing, n (%) 65 (40.4) 4 (23.5) 16 (100.0) 85 (43.8) wound/surgical site, n (%) NA 7 (41.2) NA 7 (41.2) missing/unknown, n Infection site a limbs, n (%) 100 (69.9) 3 (16.7) 8 (47.1) 111 (62.4) head/neck, n (%) 9 (6.3) 0 4 (23.5) 13 (7.3) perineum/genitals, n (%) 10 (7.0) 5 (27.8) 2 (11.8) 17 (9.6) other, n (%) 34 (23.8) 10 (55.6) 3 (17.6) 47 (26.4) missing/unknown, n Severity of infection deep soft tissue, n (%) 133 (82.6) 4 (22.2) 11 (64.7) 148 (75.5) missing/unknown, n requiring surgery, n (%) 122 (75.3) 6 (33.3) 8 (47.1) 136 (69.0) missing/unknown, n NA, not available. Percentages were calculated for patients with non-missing data only. a Patients could have more than one infection subtype or site. ii19

6 Montravers et al. Table 3. Prescription of tigecycline, alone or in combination, in patients with cssti Germany Italy Spain-1 France Spain-2 Number of patients Standard dosage, n (%) 142 (87.1) 41 (100.0) 16 (88.9) 16 (94.1) 15 (100.0) 230 (90.6) Duration (days), mean (range) a 12.2 (2 47) 11.3 (5 29) 10.6 (3 22) 9.8 (1 17) 14.9 (5 50) 12.0 (1 50) Therapy regimen first-line, n (%) 75 (46.0) 24 (58.5) b 2 (11.1) 8 (53.3) 3 (20.0) b 112 (44.4) b second-line, n (%) 88 (54.0) 17 (41.5) b 16 (88.9) 7 (46.7) 12 (80.0) b 140 (55.6) b missing/unknown, n monotherapy, n (%) 119 (73.9) 39 (95.1) 11 (61.1) 8 (47.1) 4 (26.7) 181 (71.8) in combination with other antibacterials, n (%) 42 (26.1) 2 (4.9) 7 (38.9) 9 (52.9) 11 (73.3) 71 (28.2) missing/unknown, n Percentages were calculated for patients with non-missing data only. a Only patients who received a standard dosage regimen of tigecycline were included. b Includes study-level data from Italy and Spain-2. Table 4. Antibacterial agents used in combination with tigecycline for treatment of patients with cssti Germany Italy Spain-1 France Spain-2 Number of patients receiving combination therapy a Agent, n (%) b third-/fourth-generation cephalosporins 15 (35.7) NA 1 (14.3) 2 (22.2) 1 (9.1) 19 (27.5) ceftazidime 13 (31.0) NA 1 (14.3) 1 (11.1) 0 15 (21.7) cefepime 2 (4.8) NA (9.1) 3 (4.3) aminoglycosides 1 (2.4) NA 2 (28.6) 3 (33.3) 3 (27.3) 9 (13.0) carbapenems 9 (21.4) NA 1 (14.3) 0 1 (9.1) 11 (15.9) fluoroquinolones 10 (23.8) NA 0 4 (44.4) 1 (9.1) 15 (21.7) ciprofloxacin 7 (16.7) NA 0 3 (33.3) 1 (9.1) 11 (15.9) glycopeptides 1 (2.4) NA 1 (14.3) 0 1 (9.1) 3 (4.3) metronidazole 3 (7.1) NA 2 (28.6) 1 (11.1) 2 (18.2) 8 (11.6) piperacillin/tazobactam 1 (2.4) NA 0 3 (33.3) 2 (18.2) 6 (8.7) NA, not available. Percentages were calculated for patients with non-missing data only. a Denominator for percentage calculations in the total column (n¼69) does not include patients from Italy. b Patients could receive more than one antibacterial in combination with tigecycline. stratified by APACHE II score, the pooled data showed that there was a trend towards higher response rates in patients with lower versus higher APACHE II scores at baseline (Table 6). Overall, 75.3% of 81 patients with an APACHE score.15 showed a response (compared with 82.7% who scored 15); 12 patients (14.8%) with an APACHE II score.15 were classified as non-responders and 8 (9.9%) had an indeterminate outcome. Among 12 patients in France and Spain-2 with a SOFA score 7 there were 7 responders (58.3%), 2 (16.7%) non-responders and 3 (25.0%) with an indeterminate outcome. Community-acquired infections were associated with slightly higher response rates [85.1% (86/101)] than those acquired in hospital [75.0% (96/128)]; 19 patients (14.8%) with nosocomial infections were classified as nonresponders and 13 (10.2%) had an indeterminate outcome (Figure 3). When tigecycline was given as monotherapy, 86.7% (143/165) of patients responded to this treatment [13 patients (7.9%) were classified as non-responders and 9 (5.5%) had an indeterminate outcome] (Figure 4). The clinical response rate was 85.5% for patients treated with tigecycline as first-line therapy and 78.1% for those treated with tigecycline as second-line therapy (Table 6). ii20

7 Efficacy of tigecycline for complicated skin and soft-tissue infections in Europe JAC Table 5. Reasons for tigecycline use, alone or in combination, in patients with cssti Germany Italy Spain-1 France Spain-2 Number of patients Reason, n (%) a failure of previous therapy b 86 (52.8) 11 (26.8) c 9 (50.0) 3 (17.6) 3 (20.0) c 112 (44.1) c suspicion of resistant pathogens 83 (50.9) 7 (17.1) c 2 (11.1) 7 (41.2) 2 (13.3) c 101 (39.8) c need broad-spectrum coverage/polymicrobial infection 79 (48.5) NA 8 (44.4) 8 (47.1) 9 (60.0) c 104 (48.8) c allergy to/intolerance of previous antibacterial 2 (1.2) 6 (14.6) c 1 (5.6) 0 2 (13.3) c 11 (4.3) c renal impairment NA NA NA 2 (11.8) 2 (13.3) c 4 (12.5) c other NA 17 (41.5) c NA 3 (17.6) 2 (13.3) c 22 (30.1) c NA, not available. Percentages were calculated for patients with non-missing data only. a Patients could have more than one reason. b Previous therapy includes all treatments that were given prior to the patient s admission to hospital with cssti. c Includes study-level data from Italy and Spain-2. Table 6. Clinical response at EOT in patients with cssti who received the standard dose of tigecycline alone or in combination Germany Italy Spain-1 France Spain-2 Clinical response by disease severity number of patients NA APACHE II 15, n/n (%) 48/56 (85.7) 31/39 (79.5) 3/3 (100.0) 4/6 (66.7) 86/104 (82.7) APACHE II.15, n/n (%) 55/71 (77.5) 1/2 (50.0) 0 5/8 (62.5) 61/81 (75.3) number of patients NA NA NA SOFA,7, n/n (%) 7/10 (70.0) 6/9 (66.7) 13/19 (68.4) SOFA 7, n/n (%) 3/6 (50.0) 4/6 (66.7) 7/12 (58.3) Clinical response by therapy regimen number of patients 142 NA NA 172 first-line, n/n (%) 58/66 (87.9) 1/2 (50.0) 6/8 (75.0) 65/76 (85.5) second-line, n/n (%) 58/76 (76.3) 14/14 (100.0) 3/6 (50.0) 75/96 (78.1) NA, not available. Percentages were calculated for patients with non-missing data only. Response was defined as clinical cure or improvement without additional antibiotic. Safety profile and patient discontinuation Data on all-cause AEs, SAEs and reasons for discontinuation were documented in three studies (Germany, Spain-1 and France) for 198 cssti patients who received tigecycline alone or in combination. Altogether, 90 AEs were experienced by 49 patients (24.7%); SAEs were reported in 29 patients (14.6%). Among the patients who discontinued their tigecycline treatment (37/196 patients, 18.9% across three studies), the frequently reported reasons were clinical failure (37.8%) and microbiological failure (2.7%). Data on mortality were available from all five studies for 254 cssti patients. Overall there were 24 patients who died from any cause at any time during the study, including the follow-up period, giving a mortality rate of 9.4%. The mortality rate was higher in patients with higher (.15) versus lower ( 15) baseline APACHE II scores (18.7% versus 3.5%, respectively). The numbers were too small to make an evaluation by baseline SOFA scores. Further data on the safety and tolerability profile of tigecycline in these observational studies are provided by Guirao et al. 29 Discussion In this analysis, we investigated the real-life clinical use of tigecycline for the treatment of hospitalized patients with cssti in four European countries. All the studies were observational and non-interventional in nature, thus documenting the efficacy of tigecycline in routine clinical practice. In particular, we were interested in analysing the type, severity and microbiology of ii21

8 Montravers et al. Response Non-response Indeterminate Monotherapy Combination therapy Clinical outcome (%) Germany (n = 142) Italy (n = 41) 93.8 Spain-1 France Spain-2 (n = 15) (n = 230) patients infections, their concomitant treatment with other antibiotics, the specific reasons for tigecycline administration, the doses that were given and the clinical outcome and safety with tigecycline. In the five studies conducted in Europe, patients with cssti accounted for 14.3% of all patients treated with tigecycline. Of these patients, the vast majority received the standard dosage of tigecycline for a mean duration of 12.0 days, and overall Figure 2. Clinical outcome at EOT in patients with cssti who received the standard dose of tigecycline alone or in combination. Percentages were calculated for patients with non-missing data only. Response was defined as clinical cure or improvement without additional antibiotic. Non-response was defined as failure or improvement with additional antibiotic. Patients whose response could not be ascertained were assigned an indeterminate outcome. Clinical response (%) Germany (n = 141) Italy (n = 41) Community Spain-1 Nosocomial France Spain-2 (n = 15) (n = 229) Figure 3. Clinical response by mode of infection acquirement in patients with cssti who received the standard dose of tigecycline alone or in combination. Percentages were calculated for patients with non-missing data only. Response was defined as clinical cure or improvement without additional antibiotic. Clinical response (%) Germany (n = 140) Italy (n = 41) Spain France Spain-2 (n = 15) (n = 228) 71.8% received tigecycline as monotherapy. However, there were differences between the studies in the percentage of patients treated with tigecycline as monotherapy or in combination with other antibacterials. The highest percentage of combination therapy was recorded in Spain-2, where all of the patients were in the ICU and almost all the infections were nosocomial. Overall, the study population comprised patients with complicated infections and high disease severity, as evidenced by mean APACHE II scores.15 and mean SOFA score 7 for more than 40% of those studied. Many of the patients were critically ill in the ICU, and the majority had been previously treated with other antibiotics and had at least one comorbid condition, including 44.2% with renal insufficiency. The cssti patients in these five studies represented a range of clinical presentations, with all of the patients from France in the ICU with necrotizing infection, while in Spain-1 many patients had wound/surgical site infections and were not in the ICU. csstis can be challenging to treat, not only due to the variation in clinical presentations, but also because of the bacteria that can be involved, including multidrug-resistant Gram-positive and Gram-negative pathogens. In this observational analysis, the main reasons for use of tigecycline in patients with cssti were for the treatment of polymicrobial infection, suspicion of resistant pathogens and failure of previous therapy. This real-life clinical practice is consistent with current international guidelines recommending tigecycline for polymicrobial infections that may include MRSA, and for necrotizing fasciitis. 2 Susceptibility tests have shown tigecycline to have a broad spectrum of activity against multiple pathogens, including resistant strains that may be present in cssti such as MRSA, VRE, ESBL-producing strains or Klebsiella pneumoniae positive for carbapenemase, as well as anaerobes that may be isolated from necrotizing infections. 6 Additionally, in this analysis 12.5% of cssti patients were treated with tigecycline because of renal insufficiency. Patients with impaired renal function have a high risk for the development of infection, and the loss of renal function can affect the Figure 4. Clinical response in patients with cssti who received the standard dose of tigecycline alone or in combination. Percentages were calculated for patients with non-missing data only. Response was defined as clinical cure or improvement without additional antibiotic. ii22

9 Efficacy of tigecycline for complicated skin and soft-tissue infections in Europe JAC efficacy of antimicrobial therapy if optimal drug levels are not maintained. 30 As tigecycline is eliminated primarily by biliary/ faecal excretion, no dosage adjustment is needed in patients with renal impairment or in patients undergoing dialysis. 11 As expected, many patients had more than one pathogen identified at baseline. S. aureus was the most common pathogen isolated in over half of the patients, and a large proportion of these isolates were MRSA. Gram-negative infections were less common, but involved a range of pathogens, including E. coli, Enterobacter spp., Proteus mirabilis, K. pneumoniae, A. baumannii and P. aeruginosa, as well as the anaerobic bacillus Bacteroides fragilis, which was isolated from two patients in Germany. 28 This documented range of infections possibly reflects the variation in epidemiology of multidrug-resistant pathogens across Europe. Tigecycline has shown good in vitro activity against these pathogens; however, it is not active against P. aeruginosa. 6 Despite the fact that many of the patients were critically ill and requiring ICU care, or had high APACHE II or SOFA scores at the time of tigecycline administration, the overall clinical outcomes were good, and largely in the range of previously reported results with tigecycline in Phase III trials with populations showing substantially lower mean APACHE II scores A successful clinical response was observed for 79.6% of all cssti patients who received tigecycline alone or in combination pooled across the five European studies compared with 82% in the pooled tigecycline patients of the two pivotal skin and softtissue infection trials. 15 In this multinational analysis, clinical response rates varied across studies and were lowest (62.5%) in the study from France and highest (93.8%) in the study from Spain-1. The difference in response rates between studies probably reflects the differences in the patient populations, as 100.0% of the patients in the study from France and Spain-2 were from the ICU compared with only 5.6% in Spain-1. These findings are also consistent with the observed trend towards lower response rates in patients with higher disease severity (e.g. 75.3% in patients with an APACHE II score.15 compared with 82.7% in patients with a score 15). We also observed a trend towards lower response rates for nosocomial versus community-acquired csstis (75.0% versus 85.1%) and for patients treated with combination therapy versus monotherapy (63.5% versus 86.7%). The less favourable clinical outcome amongst patients who received combination therapy could be explained by a potential bias within the groups. It is possible that these patients were experiencing more severe disease or might have been at an increased risk of Pseudomonas infection, hence their requirement for a combination of antibiotics as this pathogen is not covered by tigecycline. In these non-interventional studies, the use of tigecycline for the approved indication of cssti was well tolerated. When taking into account the disease severity of these patients and the proportion who had been admitted to the ICU, the frequency of SAEs was within the expected range. The pooled analysis showed a trend towards higher mortality in patients with high APACHE II or SOFA scores at the start of tigecycline therapy. Additionally, assuming that the probability of the occurrence of a fatal outcome is around 21.0% for a patient with cssti having a disease severity score close to the mean value found in our observational studies (estimated APACHE II score of 15), 31 the observed actual mortality rate (9.4%) was lower than expected in the tigecycline-treated patients. This analysis has several limitations, and the results should be viewed as descriptive due to the observational, noninterventional and non-comparative design of each study. There was variation in the study designs: four of the studies were prospective, one was retrospective and one was from a single centre. The data are complex to interpret, particularly given the heterogeneity in countries, sites, hospitals and patient care. Two studies included primarily critically ill patients from the ICU, whereas three studies also included patients from surgical wards with a broader range of disease severity scores. The modality of treatment with tigecycline also varied across studies: in Italy, very few patients were prescribed tigecycline in combination with other antibiotics compared with Spain-2. Another source of heterogeneity in the treatment of these patients is whether tigecycline was given as first- or second-line treatment. The different practices of physicians in these studies may well reflect the differing epidemiology of multidrug-resistant pathogens, which varies across Europe, leading to differences in the clinical approach to empirical antibacterial treatment. In summary, these real-life observational studies in Europe included a higher proportion of seriously ill patients than was captured in the Phase III registration trials of tigecycline. In these patients tigecycline, alone and in combination, achieved favourable clinical response rates in the treatment of csstis. We believe that this analysis adds important information for the antibacterial management of this group of patients, who have a substantial morbidity and mortality. Acknowledgements We thank all the investigators who documented the patients in these observational studies. Funding The studies from Germany (NCT ), France (NCT ) and Spain-1 (NCT ) were supported by Wyeth Pharma (now Pfizer). The study from Spain-2 (performed by the Spanish ICU Tigecycline Study Group) and the study from Italy were conducted independently and received no financial support. The editorial support was funded by Pfizer International Operations. Transparency declarations This article is part of a JAC Supplement sponsored by Pfizer International Operations. P. M. has received research grant support and consultancy and/or speaker fees from Astellas, AstraZeneca, Gilead, Merck Sharp & Dohme and Pfizer. M. B. has received research grant support from Pfizer and Merck Sharp & Dohme, and consultancy and/or speaker fees from Angelini, Astellas, AstraZeneca, Gilead, Merck Sharp & Dohme, Novartis, Pfizer and Teva. H. D. has received research grant support from Pfizer and consultancy and/or speaker fees from Astellas, Merck Sharp & Dohme and Pfizer. C. E. has received research grant support from Wyeth (now Pfizer) and consultancy and/or speaker fees from AstraZeneca, Bayer, Merck Sharp & Dohme, Novartis, Pfizer and Wyeth. W. R. H. has received research grant support from Wyeth (now Pfizer) and consultancy and/or speaker fees from Bayer and Pfizer. X. G. has received research grant support from Wyeth (now Pfizer) and consulting fees from ii23

10 Montravers et al. Pfizer. M. S. G. has received research grant support and consultancy fees from Pfizer. M. R. C. and D. S. are employees of and stockholders in Pfizer. K. F. B. has received research grant support from Wyeth (now Pfizer) and consulting fees from Pfizer. Statistical support for the pooled analyses was provided by Michele Wible of Pfizer. Editorial support for this manuscript was provided by J. Turner and K. Bradford, of PAREXEL. References 1 Dryden MS. Complicated skin and soft tissue infection. J Antimicrob Chemother 2010; 65 Suppl 3: iii May AK, Stafford RE, Bulger EM et al. Treatment of complicated skin and soft tissue infections. Surg Infect (Larchmt) 2009; 10: Eron LJ, Lipsky BA, Low DE et al. Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother 2003; 52 Suppl 1: i Moet GJ, Jones RN, Biedenbach DJ et al. 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