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The Efficacy and Safety of Tigecycline in the Treatment of Skin and Skin-Structure Infections: Results of 2 Double-Blind Phase 3 Comparison Studies with Vancomycin-Aztreonam

  1. E. J. Ellis Grosse1,
  2. T. Babinchak1,
  3. N. Dartois2,
  4. G. Rose1,
  5. E. Loh1, and
  6. Tigecycline 300 and 305 cSSSI Study Groupsa
  1. 1Medical Research Group, Wyeth Research, Collegeville, Pennsylvania
  2. 2Wyeth, Paris, France
  1. Reprints or correspondence: Dr. Evelyn J. Ellis-Grosse, Wyeth Research, 500 Arcola Rd., Collegeville, PA 19426 (ellise{at}wyeth.com).

  • ↵Presented in part: 11th International Symposium on Staphylococci and Staphylococcal Infections, Charleston, South Carolina, 24–27 October 2004 (control TH-130); 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 30 October–2 November 2004 (session 97/control 2875, L-986).

 
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Abstract

Two phase 3, double-blind studies in hospitalized adults with complicated skin and skin-structure infections (cSSSI) determined the safety and efficacy of tigecycline versus that of vancomycin-aztreonam. Patients received tigecycline (100 mg, followed by 50 mg intravenously twice daily) or vancomycin (1 g intravenously twice daily) plus aztreonam (2 g intravenously twice daily) for up to 14 days. Populations were as follows: 1116 patients (566 treated with tigecycline, and 550 treated with vancomycin-aztreonam) constituted the modified intent-to-treat (mITT) population, 1057 patients (538 treated with tigecycline, and 519 treated with vancomycin-aztreonam) constituted the clinical mITT (c-mITT) population, and 833 patients (422 treated with tigecycline, and 411 treated with vancomycin-aztreonam) constituted the clinically evaluable population. Clinical responses to tigecycline and vancomycin-aztreonam at test-of-cure were similar: c-mITT, 79.7% (95% confidence interval [CI], 76.1%–83.1%) versus 81.9% (95% CI, 78.3%–85.1%) (P = .4183); and clinically evaluable, 86.5% (95% CI, 82.9%–89.6%) versus 88.6% (95% CI, 85.1%–91.5%) (P = .4233). Adverse events were similar, with increased nausea and vomiting in the tigecycline group and increased rash and elevated hepatic aminotransferase levels in the vancomycin-aztreonam group. Tigecycline monotherapy is as safe and efficacious as the vancomycin-aztreonam combination in treating patients with cSSSI.

Serious skin and skin-structure infections caused by multidrug-resistant pathogens have become more common over the last decade, suggesting that alternative empirical treatment measures may be needed for at-risk patients. Patients are considered to have complicated skin and skin-structure infections (cSSSIs) when there is a need for surgical intervention, if deep soft tissue involvement is suspected or confirmed, and/or when the patient has a complicating condition, such as diabetes mellitus, peripheral vascular disease, or peripheral neuropathy [1–3]. cSSSIs typically are characterized by a diverse polymicrobial etiology. Staphylococcus aureus, Streptococcus pyogenes (group A β-hemolytic streptococci), or Streptococcus agalactiae (group B β-hemolytic streptococci) are the pathogens most frequently isolated from immunocompetent patients with cSSSIs [4, 5]. However, patients with an underlying comorbidity that compromises their immune system often have infection with difficult-to-treat or multidrug-resistant aerobic and anaerobic gram-positive and gram-negative bacteria [3].

Selection of an optimal empirical antibiotic regimen for cSSSIs is challenging. The emergence of methicillin-resistant S. aureus (MRSA) in the hospital setting [6], and more recently in the community [7], has added to this difficulty. Notably, community-acquired MRSA strains are most commonly linked to skin and soft tissue infections [7]. It is also appreciated that inadequate coverage may lead to undesirable outcomes (e.g., development of antimicrobial resistance and clinical failure) [8–10]. The appearance of vancomycin-resistant S. aureus escalates the need for new first-line therapies that are effective against suspected skin pathogens, including resistant organisms [11, 12].

Tigecycline is a first-in-class, expanded broad-spectrum glycylcycline [13] antibiotic that was designed to circumvent 2 common tetracycline resistance mechanisms in bacteria (i.e., efflux and ribosomal protection) [14]. As such, the activity of tigecycline is unaffected by the presence of extended-spectrum β-lactamases, penicillin-binding protein mutations, or gyrase mutations [15–17]. Tigecycline has broad in vitro activity against both susceptible bacteria and multidrug-resistant bacteria commonly associated with cSSSIs, including MRSA, methicillin-susceptible S. aureus, vancomycin-resistant enterococci, Escherichia coli, Enterococcus species, Bacteroides species, Clostridium difficile, and Peptostreptococcus species [17–21].

The pooled analysis reported here primarily describes the findings of 2 independent, phase 3, double-blind, randomized trials [22, 23] that compared the clinical efficacy and safety of tigecycline monotherapy with that of the combination of vancomycin and aztreonam in hospitalized patients with cSSSIs. Secondary goals were to compare the microbiological efficacy between treatment groups and to obtain additional in vitro susceptibility data about tigecycline for a range of bacteria that cause cSSSIs. Pooling of the 2 studies is justified, because both studies had similar study design and methodology, and because treatment group-by-protocol and treatment group-by-geographic region interaction effects were tested at the .10 level of significance, but no significant interactions were detected.

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Patients And Methods

Study design and treatment. Two phase 3, randomized, double-blind studies were conducted among patients with cSSSIs from August 2001 to February 2004. The North American/South American study was conducted in 53 centers in 8 countries (United States, Canada, Argentina, Chile, Guatemala, Mexico, Peru, and India), whereas the worldwide study was conducted in 65 centers in 21 countries in Europe, Asia, Australia, and South Africa. The protocols were reviewed and approved by the institutional review board or ethical review committee at each participating center. Written informed consent was obtained from each patient or from the patient's guardian before the start of any study procedures, according to the guidelines of each institution. The trials were conducted in accordance with the Declaration of Helsinki and its amendments.

Before the pooled analyses were made on the primary efficacy variable, the appropriateness of pooling the data was examined by using a generalized linear model (for adjusted differences) and an interaction model with the following factors: protocol, treatment, and protocol-by-treatment interaction (significant at the <.10 level). Results showed that the protocol-by-treatment interaction for clinical response was not significant at the test-of-cure assessment, which suggests that the pooling of data from these studies is appropriate. Similar results were observed when interaction effects for treatment group by protocol on microbiological response were examined for the microbiologically evaluable population.

Patients were randomly assigned (1 : 1) to receive tigecycline with placebo or the combination of vancomycin-aztreonam intravenously for up to 14 days. For patients assigned to the tigecycline group, the initial intravenous dose of 100 mg of tigecycline was followed by 50 mg every 12 h in 250 mL of normal saline infused for 60 min. After each tigecycline infusion, patients received 100 mL of normal saline placebo infused for 60 min, to maintain the study blinding, because of the need for combination therapy in the comparator group. For patients assigned to the combination vancomycin-aztreonam group, 1 g of vancomycin in 250 mL of normal saline was to be administered intravenously for 60 min, followed by the administration of 2 g of aztreonam in 100 mL of saline for 60 min, each every ∼12 h. Vancomycin dosage could be adjusted according to creatinine clearance values for patients with compromised renal function, as suggested by the vancomycin label [24]. Aztreonam could be discontinued after 48 h, per the investigator's clinical judgment.

Inclusion and exclusion criteria. Eligible patients were hospitalized men and women aged ⩾18 years with cSSSIs that either involved deep soft tissue (including extensive cellulitis at least 10 cm in width or length), required surgical intervention, or was associated with significant underlying disease (e.g., diabetes mellitus, peripheral vascular disease, peripheral neuropathy, or lower venous insufficiency). In addition to the infection, the patient had to have at least 2 of the following signs and symptoms: drainage or discharge, fever, erythema, swelling, localized warmth, pain, and/or WBC count of >10,000 cells/mm3. After the original sample was obtained for culture, patients received no more than 2 doses of nonstudy antibacterial therapy. If a patient was considered to have experienced prior antibiotic failure, a Gram stain showing a potential isolate or a sample for culture from the infected site was obtained at baseline before administration of study drug. Patients satisfying the above criteria were enrolled if they required intravenous antibiotic therapy for a minimum of 5 days.

Patients were excluded if they had necrotizing fasciitis, gangrene, osteomyelitis, plasmapheresis, hemoperfusion, neutropenia, severely impaired arterial blood supply, or any condition or medication that would impair the ability to eradicate infections. If a patient had an uncomplicated skin or skin-structure infection (e.g., simple abscesses, folliculitis, impetiginous lesions, furunculosis, or superficial cellulitis) or an infection that could be treated by surgery alone, patients were also excluded from the study. In addition, patients were excluded for any of the following reasons: presence of hepatic disease (aspartate aminotransferase or alanine aminotransferase level >10 times the upper limit of normal, bilirubin level >3 times upper limit of normal, or presence of acute hepatic failure or acute decompensation of chronic hepatic failure); history of hypersensitivity to tigecycline, vancomycin, aztreonam, or tetracycline agents; or a known or suspected concomitant infection that required treatment with another antimicrobial agent.

Analysis populations. Patients meeting the inclusion and exclusion criteria were included in the intent-to-treat (ITT) population. Those who received at least 1 dose of study drug constituted the modified ITT (mITT [or safety]) population, and patients in the mITT population who had clinical evidence of a cSSSI by meeting the minimal disease criteria made up the clinical modified ITT (c-mITT) population.

Patients in the c-mITT population were considered to be clinically evaluable if they did not have Pseudomonas aeruginosa as a sole baseline isolate, received no concomitant antibiotic after their first dose of study medication (tigecycline or vancomycin-aztreonam), and had an assessment of cure or failure at the test-of-cure visit. The microbiologically evaluable population included clinically evaluable patients for whom ⩾1 causative isolate was identified from the baseline culture and who had a microbiological response at the test-of-cure visit.

Clinical and microbiological assessments. An investigator blinded to treatment assessed drainage and/or discharge, fever, erythema, swelling and/or induration, pain and/or tenderness to palpation, extent of infection (width and length), and localized warmth. On the basis of these assessments, the investigator evaluated the patient's clinical response to therapy at the test-of-cure visit as “cure” if the patient had resolution of signs and symptoms such that no further antibiotic therapy was required; “failure” if the patient had an inadequate response to therapy requiring additional antibiotic therapy at any point during the study or required an unplanned surgical intervention; or “indeterminate” if no evaluation was possible for any reason (e.g., loss to follow-up).

Microbiological efficacy was evaluated at both the patient (eradication, persistence, superinfection, or indeterminate) and isolate level (eradication, persistence, or indeterminate). Skin cultures were the principal source of the baseline isolate; however, a blood isolate could be used if no baseline isolate was identified from the skin source. All specimens (blood cultures and aerobic and anaerobic cultures from the primary site of infection) were sent to local laboratories for primary identification of the isolates and were tested for susceptibility to tigecycline by the Kirby-Bauer disk diffusion test. Recovered isolates were subcultured and tested for susceptibility at a central laboratory by both microbroth dilution tests, to determine the MIC, and Kirby-Bauer disk diffusion tests, according to procedures published by the NCCLS [25–27]. The provisional MIC break points for tigecycline were based on previous preclinical investigations, as follows: ⩽2 mg/L, susceptible; >2 to <8 mg/L, intermediate; and ⩾8 mg/L, resistant. MIC50 and MIC90 values were determined for each study drug for the most common isolates, as well as selected known resistant isolates (e.g., MRSA and vancomycin-resistant enterococci).

Evaluation of safety and tolerability. Safety assessments included a physical examination and 12-lead electrocardiography at baseline. Vital signs (temperature, heart rate, and blood pressure) and routine clinical laboratory parameters (hematology, blood chemistry evaluations, coagulation parameters, and urinalysis) were assessed at each scheduled evaluation. Adverse events were recorded throughout the study period, up to and including the test-of-cure visit. Before unblinding, the investigator categorized the severity of each adverse event and the relationship to study drug. Treatment-emergent adverse events were defined as those that appeared or worsened 5 days after the last day of drug therapy.

Statistical analysis. Clinical response within the clinically evaluable and c-mITT populations at the test-of-cure visit (12–92 days after the last dose) was the primary efficacy end point. Secondary analyses included microbiological response at the test-of-cure visit by patient and isolate, as well as clinical response rates stratified as monomicrobial versus polymicrobial, and by isolate.

Statistical analysis was done by the Clinical Biostatistics Department of Wyeth Research (Collegeville, PA). Categorical baseline demographic and medical variables were analyzed by Fisher's exact test. Continuous variables were compared by 1-way analysis of variance model with treatment as a factor. Between-group comparisons of treatment-emergent adverse events were analyzed with a 2-sided Fisher's exact test. For laboratory tests, vital signs, and electrocardiographic results, within-group changes from baseline were analyzed by paired t test and between-group comparisons were made by analysis of covariance, adjusting for baseline value. The difference between treatment groups in the percentage of premature withdrawal from study drug was evaluated by a 2-sided Fisher's exact test. All significant differences were defined as P < .05.

To determine the noninferiority of tigecycline, compared with the combination of vancomycin-aztreonam, for clinical and microbiological responses, a 2-sided 95% CI for the true difference in efficacy (tigecycline minus the combination of vancomycin-aztreonam) was used. The CI was corrected for continuity. Noninferiority was concluded if the lower limit of the 2-sided 95% CI was -15% or more. For all subpopulation analyses (e.g., monomicrobial versus polymicrobial), an adjusted difference between treatment groups with its 95% CI was calculated from a generalized linear model with a binomial probability function and an identity link. For end points involving comparisons of tigecycline and the combination of vancomycin-aztreonam with small sample sizes, the method of Wilson [28], corrected for continuity, was used. The method used to compute the 2-sided 95% CI for a single proportion was the “exact” method of Clopper and Pearson [29]. P < .05 was considered to be statistically significant.

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Results

Patient disposition and analysis populations. A total of 1153 patients were screened for study participation, of whom 1129 were randomly assigned to receive tigecycline or vancomycin-aztreonam (figure 1). Thirteen patients did not receive study drug, leaving 1116 patients (566 treated with tigecycline, and 550 treated with vancomycin-aztreonam) in the mITT population. Of this latter group, 59 patients did not meet the criteria for the severity of infection, such that 1057 patients (538 treated with tigecycline, and 519 treated with vancomycin-aztreonam) made up the c-mITT population. The clinically evaluable population included 833 patients, and 769 patients had a pretherapy isolate recovered and constituted the microbiological mITT (m-mITT) population. A total of 540 patients (279 treated with tigecycline, and 261 treated with vancomycin-aztreonam) met clinical evaluability criteria and had a baseline isolate from a skin or blood source (microbiologically evaluable population). The primary reasons for exclusion from the clinically evaluable population in both treatment groups were blind broken (n = 80), entry criteria not met (n = 60), no clinical evaluation at the test-of-cure visit (n = 55), >2 doses of prior antibiotic after baseline culture obtained (n = 12), and isolation of P. aeruginosa from a baseline culture (n = 7). The rates of the reasons for exclusion were similar between treatment groups.

Figure 1
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Figure 1

Disposition of patients in studies of tigecycline versus vancomycin-aztreonam (V/A) in the treatment of skin and skin-structure infections. ITT, intent-to-treat; mITT, modified intent-to-treat.

Patient population: demographics and baseline medical characteristics. In this pooled analysis, the majority of patients were white (68.2%), were men (62.1%), and had a mean age of ∼48 years (table 1). Patients in both treatment groups had similar demographic characteristics, clinical cSSSI diagnoses, etiology of infection, and comorbid conditions (table 1). Diabetes mellitus was present in ∼20% of patients. The most common diagnosis in both groups was deep soft tissue infection involving cellulitis (approximately two-thirds of the clinically evaluable population). Approximately half of the cSSSIs were spontaneous, ∼30% were secondary to traumatic injury, and 11% were postsurgical complications. There were no significant differences between treatment groups in the number or types of cSSSIs diagnosed at baseline nor in the cause of these infections. The clinically evaluable patients received study drug treatment for an average of 8 days.

Table 1
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Table 1

Demographic and baseline characteristics of the pooled clinically evaluable population with skin and skin-structure infections (SSSIs).

Clinical outcomes. Overall, in the c-mITT population, clinical cure was reported for 79.7% of patients treated with tigecycline and for 81.9% of patients treated with vancomycin-aztreonam (95% CI for the difference, -7.1% to 2.8%; table 2). Corresponding clinical cure rates for the clinically evaluable population were 86.5% and 88.6%, respectively (95% CI for the difference, -6.8% to 2.7%). The results for these 2 primary populations met statistical criteria for the noninferiority of tigecycline to vancomycin-aztreonam and showed a lack of treatment differences between groups.

Table 2
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Table 2

Clinical cure rates by study population at the test-of-cure visit.

No significant treatment differences in clinical cure rates were observed between the groups treated with tigecycline and vancomycin-aztreonam when patients were stratified by the number of pretherapy isolates: monomicrobial versus polymicrobial (table 2). For the microbiologically evaluable population, tigecycline was associated with 86.3% and 86.4% clinical cure rates at the test-of-cure visit for monomicrobial versus polymicrobial infections, respectively. Likewise, patients treated with vancomycin-aztreonam had similar clinical cure rates when stratified by the number of recovered baseline isolates: 88.7% and 88.3%, respectively.

Clinical cure rates were also equivalent within and between the 2 treatment groups on the basis of the investigator's chief diagnoses of cSSSIs (table 3). For patients with soft tissue infections (the most common type of cSSSI), clinical cure was reported for 86.3% of patients treated with tigecycline, compared with 87.3% of patients treated with vancomycin-aztreonam. Patients with abscesses, the second most common type of infection, also had high clinical cure rates (87.1% of patients treated with tigecycline, vs. 91.4% of patients treated with vancomycin-aztreonam).

Table 3
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Table 3

Clinical cure rates by baseline diagnosis by investigator, patients with diabetes or peripheral vascular disease, or baseline bacteremia status (clinically evaluable population) at the test-of-cure visit.

Tigecycline monotherapy was comparable with vancomycin-aztreonam in the subsets of patients with concomitant bacteremia (82.6% of patients treated with tigecycline, vs. 87.5% of patients treated with vancomycin-aztreonam). For 13 tigecycline-treated patients with concomitant bacteremia (5 had >1 isolate) due to noncontaminant isolates, clinical cure was reported for 77% patients (10/13), including 80% (8/10) of patients with S. aureus and 100% (all 3) of patients with Streptococcus species isolated from blood. In addition, the treatment regimens appeared to be equally effective in those patients with baseline comorbidities of diabetes mellitus (72.3% of patients treated with tigecycline, vs. 76.5% of patients treated with vancomycin-aztreonam) and peripheral vascular disease (75.9% of patients treated with tigecycline, vs. 75.0% of patients treated with vancomycin-aztreonam).

Microbiological efficacy. The pooled analysis of microbiological response by patient shows that tigecycline was statistically noninferior to vancomycin-aztreonam in the microbiologically evaluable population at the test-of-cure visit (95% CI, -10.6% to 2.4%). The eradication rate by patient was 82.1% for those treated with tigecycline, versus 86.2% for those treated with vancomycin-aztreonam. For the m-mITT population, similar findings were observed: 76.2% for tigecycline, versus 79.1% for vancomycin-aztreonam treatment (95% CI for difference, -9.1% to 3.2%). The eradication rates of the primary baseline isolates in tigecycline-treated patients were comparable with the rates in patients who received vancomycin-aztreonam.

The eradication rates by isolate in both treatment groups are summarized in table 4. Of clinical significance was the observation that tigecycline was microbiologically effective against MRSA. In the microbiologically evaluable population, a total of 32 patients treated with tigecycline and 33 patients treated with vancomycin-aztreonam had MRSA as a baseline isolate, of which 21 (32%) were community-acquired strains (9 in patients treated with tigecycline and 12 in patients treated with vancomycin-aztreonam). Overall eradication rates for all MRSA strains were reported in 78.1% and 75.8% of tigecycline- and vancomycin-aztreonam–treated patients, respectively. Eradication for patients with community-acquired MRSA was reported for 77.8% of tigecycline- and 75.0% of vancomycin-aztreonam–treated patients. In addition, for both tigecycline-treated patients with infection due to expanded-spectrum β-lactamase–producing Proteus mirabilis, the infection was eradicated.

Table 4
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Table 4

Microbiological eradication rates of selected baseline isolates at the test-of-cure visit (microbiologically evaluable population).

MIC50 and MIC90 values were calculated for all baseline isolates obtained from patients in the microbiologically evaluable population. table 5 summarizes these values for tigecycline, vancomycin, and aztreonam against selected baseline isolates of clinical interest: methicillin-resistant and methicillin-susceptible S. aureus, S. pyogenes, S. agalactiae, Enterococcus faecalis, E. coli, and Bacteroides fragilis. Tigecycline consistently had MIC90 values of <0.5 mg/L for these most prevalent isolates. For methicillin-resistant and methicillin-susceptible S. aureus, tigecycline had a reported MIC90 of 0.25 mg/L. Overall, no isolates demonstrated the development of decreased susceptibility to tigecycline in this pooled analysis.

Table 5
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Table 5

MIC range and MIC50 and MIC90 values for selected primary baseline isolates (microbiologically evaluable population).

Safety and tolerability. Data from all 1116 patients (566 treated with tigecycline, and 550 treated with vancomycin-aztreonam) in the mITT population were analyzed for safety. Regardless of study drug causality, treatment-emergent adverse events occurred in 67.7% of patients treated with tigecycline (383/566) and in 61.1% of patients treated with vancomycin-aztreonam (336/550) (P = .024). The majority of these adverse events were not related to study medication and were mild to moderate in intensity.

Several differences in the types and frequencies of the most common treatment-emergent adverse events (i.e., occurring in ⩾3% of patients) were reported between treatment groups (table 6). A significantly higher number of tigecycline-treated patients than of those treated with vancomycin-aztreonam reported digestive-related treatment-emergent adverse events (46% vs. 21%; P < .001). Specifically, anorexia, diarrhea, dyspepsia, nausea, and vomiting occurred at significantly higher rates (P ⩽ .032) after tigecycline treatment than after vancomycin-aztreonam treatment. Although nausea and vomiting were usually related to tigecycline therapy, the majority of incidents were mild to moderate in severity (grades 1 or 2). In the vancomycin-aztreonam group, compared with the tigecycline group, a significantly higher number of treatment-emergent adverse events occurred in the skin and appendages (19.3% vs. 10.6%; P < .001) and cardiovascular system (14.7% vs. 8.8%; P = .003).

Table 6
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Table 6

Common treatment-emergent adverse events (⩾3% in either group) in the intent-to-treat population.

Patients treated with vancomycin-aztreonam also were 2–4-fold more likely to experience significant increases in liver aminotransferases (serum alanine and aspartate aminotransferase) than were patients treated with tigecycline. No hematologic or serum chemistry abnormalities were associated with the use of tigecycline.

The number of patients in the mITT population who discontinued therapy because of an adverse event was greater in the vancomycin-aztreonam group (n = 29) than in the tigecycline group (n = 20; table 7; P = .188). The highest number of withdrawals in the tigecycline group was the result of digestive system adverse events (n = 7), and the highest number of withdrawals in the vancomycin-aztreonam dose group was the result of adverse events of the skin and appendages.

Table 7
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Table 7

Number (%) of patients in the modified intent-to-treat population who discontinued treatment because of an adverse event.

Seven patients died during the studies, 6 in the tigecycline treatment group and 1 in the vancomycin-aztreonam treatment group. Each death was considered by the investigators to be definitely not related to study drug. In the tigecycline group, patients ranged in age from 48 to 73 years and died secondary to comorbid events of adenocarcinoma, cardiac arrest, duodenal ulcer perforation, hypoglycemia, myocardial infarction, pulmonary embolus, and septic shock. The patient in the vancomycin-aztreonam group who died was a 60-year-old man who died of complications related to chronic obstructive pulmonary disease and congestive heart failure.

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Discussion

The rising incidence of antibiotic-resistant gram-negative and gram-positive bacteria implicated as common etiologies in cSSSIs has led to the search for new and more potent antibiotic therapies [8, 9]. Tigecycline, a first-in-class glycylcycline, is a novel agent in development for the treatment of hospitalized patients with cSSSIs, lower respiratory tract infections, and intra-abdominal infections [22, 23, 30–32]. Notably, tigecycline is characterized by expanded broad-spectrum in vitro antibacterial activity against susceptible and resistant isolates, including MRSA, vancomycin-resistant enterococci, and numerous gram-negative bacilli and anaerobes [4, 17–20].

Findings from this pooled analysis indicate that tigecycline monotherapy for the treatment of cSSSIs is as effective as a current standard combination regimen (i.e., vancomycin and aztreonam). Tigecycline (50 mg infusion every 12 h after an initial dose of 100 mg) was as efficacious as and statistically noninferior to vancomycin-aztreonam (1 g/2 g infusion every 12 h) across several predefined patient populations (clinically evaluable, c-mITT, microbiologically evaluable, and m-mITT populations) at the test-of-cure visit. No significant differences in cure rates were seen between the 2 treatment groups when patients were infected with single or multiple bacteria attributable to their cSSSI. In addition, these efficacy findings were consistent across different types of infection and across different species of bacteria. For patients with deep soft tissue infection and abscesses, the 2 most common clinical diagnoses, tigecycline provided >86% clinical cure rates. Tigecycline also provided clinical cure rates for patients with underlying comorbidities (e.g., diabetes mellitus and peripheral vascular disease) that were similar to those for vancomycin-aztreonam. Although the numbers were relatively small, patients with bacteremia also had excellent clinical cure rates: 82.6% (19/23) for tigecycline, versus 87.5% (21/24) for vancomycin-aztreonam.

In this pooled analysis, tigecycline also demonstrated efficacy against many isolates commonly linked to cSSSIs, including S. aureus, S. pyogenes, E. coli, S. agalactiae, E. faecalis, and B. fragilis. Notably, the majority of cSSSIs in this study attributable to MRSA (78%) were eradicated after tigecycline therapy (vs. 76% with vancomycin-aztreonam). Additional studies are recommended to establish efficacy against MRSA. Tigecycline MIC90 values were consistently low for the most prevalent isolates, including methicillin-resistant and methicillin-susceptible S. aureus (MIC90, 0.25 mg/L for both). Data from this pooled analysis support in vitro observations that tigecycline has broad-spectrum activity against common isolates found in cSSSIs [4, 17–20].

Both tigecycline and vancomycin-aztreonam were generally well tolerated in this pooled analysis of >1100 patients. The number of patients reporting treatment-emergent adverse events related to the digestive tract was significantly higher in the tigecycline group (P ⩽ .032), whereas the incidences of rash, cardiovascular events, and increases in alanine and/or aspartate aminotransferase levels were significantly higher in the combination vancomycin-aztreonam group (P ⩽ .003). Although nausea and vomiting occurred at higher rates among those given tigecycline, most events were mild to moderate in intensity and rarely required the patient to stop taking the drug. These findings support previous safety data from phase 2 and 3 studies [30–37].

The desire for improved treatment outcomes, tolerability, and patient convenience (e.g., simplified antibiotic dosage regimen), coupled with need for more potent agents directed against resistant isolates, continues to spur the development of new antibiotics. The effective coverage of tigecycline in the treatment of cSSSI, as seen in this pooled analysis, suggests that tigecycline should be an important therapeutic option when clinicians consider antibiotics for the treatment of cSSSI. Tigecycline also offers the clinician a simplified monotherapeutic option, without the need for extensive laboratory monitoring as needed with the use of vancomycin. Tigecycline is a promising agent for the treatment of cSSSI, especially in a setting in which empirical coverage of gram-positive and gram-negative pathogens is warranted.

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Tigecycline 300 And 305 Csssi Study Groups Members

Members of the Tigecycline 300 cSSSI Study Group include Marc Alpert (Central Montgomery Medical Center, Lansdale, PA), Sacchidanand Aradhya (Victoria Hospital, Karnataka, India), Eduardo Arathoon (Hospital General San Juan de Dios, Guatemala, Guatemala), Alfred Augustine (Medical College and Hospital, Karnataka, India), Charles Bailey (Mission Hospital, Mission Viejo, CA), Ian Baird (Riverside Methodist Hospital, Columbus, OH), Joaquin Bernmejo (Unidade de Enfermidades Infecciosas-Hospital Espanol, Provincia de Santa Fe, Argentina), Jack Bernstein (Dayton VA Medical Center, Dayton, OH), Maria Campos (Hospital de Urgencia Asistencia Publica, Santiago, Chile), Nicolas Christou (McGill University Health Centre, Montreal), Nancy Crum (Naval Medical Center, San Diego), Daniel Curcio (Sanatorio Guemes, Buenos Aires, Argentina), Avinash Deodhar (K.E.M. Hospital, Maharashtra, India), Francois Dube (Pavillon Central, Sainte-Foy, Canada), John Embil (Health Sciences Centre, Winnipeg), Joseph Fraiz (Infectious Disease of Indiana, Indianapolis), Bruce Friedman (Joseph M. Still Burn Center, Augusta, GA), Marvin Gerson (Humber River Regional Hospital, Toronto), Donald Graham (Springfield Clinic Infectious Disease, Springfield, IL), Stephen L. Green (Hampton Roads Medical Specialists, Hampton, VA), Doria Grimard (Complexe Hospitalier de la Sagamie, Chicoutimi, Canada), Kamal Itani (VA Medical Center, Houston), Abel Jasovich (Hospital Carlos Bocalandro, Provencia de Buenos Aires, Argentina), Luis E. Jauregi-Peredo (ID Clinical Research, Toledo, OH), Robert Jones (Berk Infectious Disease Services, West Reading, PA), Stanley R. Klein (Harbor UCLA Research and Education Institute, Torrance, CA), Richard Kohler (Wishard Memorial Hospital, Indianapolis), Carlos Lovesio (Sanatorio Parque, Rosario, Santa Fe, Argentina), Sreevathsa Maddibande (M. S. Ramaiah Medical College and Teaching Hospital, Karnataka, India), Abhay Mane (Ruby Hall Clinic, Maharashtra, India), W. Scott McDonald (University of Miami, Miami), David McEniry (Infectious Limited, Tacoma, WA), Bheerappa Nagari (Nizam's Institute of Medical Sciences, Andhra Pradesh, India), Eduardo Rodriguez Noriega (Hospital Civil de Guadalajara, Guadalajara, Jalisco, Mexico), Rebeca Northland (Hospital de Carabineros, Santiago, Chile), Ciaran O'Hare (University of Oklahoma Health Sciences Center, Oklahoma City), Vishwanath Pai (Sri Ramachandra Medical College and Research Institute, Tamil Nadu, India), Michael Patzakis (Los Angeles County Hospital/University of Southern California Medical Center, Los Angeles), Robert Laurence Penn (Louisiana State University Health Science Center, Shreveport), Andre Poirier (Centre Hospitalier Regional de Trois-Rivieres, Trois-Rivieres, Canada), Michel Poisson (C.H.U.M. Hotel-Dieu de Montreal, Montreal), Annette Reboli (Cooper Hospital/University Medical Center, Camden, NJ), Stephen Sanche (Royal University Hospital, Saskatoon, Canada), Carlos Seas (Hospital Nacional Cayetano Heredia, Lima), Leon Smith (St. Michaels Medical Center, Newark, NJ), Kanchana Sundaramurthy (Apollo Hospital, Tamil Nadu, India), Osvaldo Teglia (Hospital Escuela Eva Peron, Provincia de Santa Fe, Argentina), Alan Tice (The Queen's Medical Center, Honolulu), Dean Tsukayama (Hennepin County Medical Center, Minneapolis), Subramaniam Vaidyanathan (Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India), Walter Vasen (Hospital of Gastroenterology “Carlos Bonorino Udaondo,” Ciudad de Buenos Aires, Argentina), Carlos Rodolfo Mejia Villatoro (Hospital Roosevelt, Ciudad de Guatemala, Guatemala), Karl Weiss (Hopital Maisonneuve-Rosemont, Montreal), and David Young (University of California–San Francisco, San Francisco).

Members of the Tigecycline 305 cSSSI Study Group include Mickael Aoun (Institut Jules Bordet, Bruxelles, Belgium), Eugeniusz Baran (Akademia, Medyczna we Wroclawiu, Wroclaw, Poland), Giedrius Barauskas (Kaunas Medicine University Hospital, Kaunas, Lithuania), Andrei Bazarov (Burdensko Main Military Clinical Hospital, Moscow), Miles Beaman (Fremantel Hospital, Fremantle, Australia), Johannes Breedt (Eugene Marais Hospital, Pretoria, Republic of South Africa), José María Callejas Pérez (Hospital Germans Trias i Pujol, Barcelona), Patrick Carroll (Redcliffe Hospital, Redcliffe, Australia), Petr Cech (Thomayer University Hospital, Kre, Czech Republic), Chia-Ming Chang (National Cheng Kung University Hospital, Tainan, Taiwan), Valeriy Chernyak (Cherkassy Regional Hospital, Cherkassy, Ukraine), Mircea Dan Chiotan (National Institute of Infectious Diseases, Bucharest, Romania), Yin-Ching Chuang (Chi Mei Medical Center, Tainan, Taiwan), Emil Lyubomirov Danchev (Multiprofile Hospital for Active Treatment “St. Anna,” Varna, Bulgaria), Georgi Petrov Deenitchin (Multiprofile Hospital for Active Treatment “St. Georgi,” Plovdiv, Bulgaria), Pierre Johannes Truter de Villiers (Hottentots Holland Hospital, Somerset West, Republic of South Africa), Jitka Dobesova (University Hospital Olomouc, Olomouc, Czech Republic), Marek Dobosz (Szpital Miejski w Gdyni, Gdansk, Poland), Matthew Dryden (Royal Hampshire County Hospital, Winchester, United Kingdom), Carmen Fariñas Alvaréz (Hospital Marques de Valdecilla, Santander, Spain), Georgi Ivanov Fichev (Multiprofile Hospital for Active Treatment “N. I. Pirogov,” Sofia, Bulgaria), Ioan Florescu (Emergency Clinical Hospital, Bucharest, Romania), Peter Fomin (National Medical University, Kyiv, Ukraine), Janis Gardovskis (P. Stradins Clinical University Hospital, Riga, Latvia), Helen Giamarellou (Sismanoglion General Hospital, Athens, Greece), David Gordon (Flinders Medical Center, Bedford Park, Australia), Audrius Gradauskas (Vilnius City University Hospital, Vilnius, Lithuania), Georgi Borisov Gurbev (Military Medical Academy, Sofia, Bulgaria), Shervanthi Homer-Vanniasinkam (Leeds General Infirmary, Leeds, United Kingdom), Christian Joukhadar (University Hospital Vienna, Vienna, Austria), Andrzej Kaszuba (Klinika Dermatologiczna, Lodz, Poland), Helmut Kerl (University Hospital Graz, Graz, Austria), Natalia Klimusheva (Regional Hospital, Ekaterinburg, Russia), Krzysztof Kolomecki (Klinika Chirurgii Endokrynologicznej i Ogolnej AM w Lodzi, Lodz, Poland), Peter Kujath (Universitaetsklinik Luebeck, Luebeck, Germany), Uldis Kupcs (Valmeira Hospital, Valmeira, Latvia), Lenoid Laberco (Moscow City Clinical Hospital, Moscow), Frans Jacobus Maritz (Tijger Trial Centre, Bellville, Republic of South Africa), John McBride (Cairns Base Hospital, Cairns, Australia), José Mensa Pueyo (Hospital Clinic i Provincial de Barcelona, Barcelona), Du san Mistuna (University Hospital Martin, Martin, Slovak Republic), Borislav Tzvetanov Ninov (Multiprofile Hospital for Active Treatment, Pleven, Bulgaria), Attila Olah (Petz Aladar Hospital, Gyor, Hungary), Remus Orasan (County Hospital Cluj-Napoca, Cluj-Napoca, Romania), Andrejs Pavars (Riga 1st Hospital Surgical Clinic, Riga, Latvia), George Petrikkos (Laikon Hospital, Athens), Waldemar Placek (Akademia Medyczna im. L. Rydygiera w Bydogoszczy, Bydgoszcz, Poland), T. Polyakova (Far-East Medical Centre, Khabrovsk, Russia), Guntars Pupelis (Clinical Hospital “Gailezers,” Riga, Latvia), Willem Jacobus Rabie (National Hospital, Bloemfontein, Republic of South Africa), Arturas Razbadauskas (Klaipeda Seaman's Hospital, Klaipeda, Lithuania), Brent Richards (Gold Coast Hospital, Southport, Australia), Douglas Patrick Ross (St. Mary's Hospital, Durban, Republic of South Africa), Sorin Rugina (Clinical Municipal Hospital Constanta, Constanta, Romania), Luis Salmeron Febres (Hospital Clinico San Cecilio, Granada, Spain), Oleg Samoylov (Clinical Hospital, Moscow), Gerhard Tappeiner (University Hospital Vienna, Vienna), Boris Teleshov (ZYL Clinical Hospital, Moscow), Jüri Teras (North Estonian Regional Hospital, Tallinn, Estonia), Milan Travnik (Public Hospital Na Homolce, Roentgenova, Czech Republic), Eugene Tretiakov (Regional Hospital No. 1 Ekaterinburg, Ekaterinburg, Russia), Sergei Turkov (Regional Hospital No. 1 Keterinburg, Ekaterinburg, Russia), Tiit Vaasna (Tartu University Clinics, Tartu, Estonia), and Dah-Shyong Yu (Tri Services General Hospital, Neiku Taipei, Taiwan).

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Acknowledgments

We thank Wyeth Research employee Patricia Bradford for microbiological analysis and Upside Endeavors for professional medical writing services.

Financial support. Wyeth Research.

Potential conflicts of interest. E.J.E.-G., T.B., N.D., G.R., and E.L. are employees of Wyeth.

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Footnotes

  • Study group members are listed after the text.

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  1. Clin Infect Dis. (2005) 41 (Supplement 5): S341-S353. doi: 10.1086/431675
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