General Methodological Considerations

Patient Analysis Populations²⁵

The randomized, or intent-to-treat (ITT), population included screened subjects who were randomly assigned to study drug or who were enrolled in an open-label study.

The modified intent-to-treat (mITT) population included ITT subjects who received at least one dose of study drug.

The clinical modified intent-to-treat (c-mITT) population included all subjects who received at least one dose of study drug and who had clinical evidence of a cSSSI, as defined in the inclusion criteria.

The clinically evaluable (CE) population included c-mITT subjects who met the following criteria: met inclusion and exclusion criteria as stated in the final amended protocol; did not have Pseudomonas aeruginosa isolated at baseline as the primary pathogen; received no more than 2 doses of a potentially effective concomitant antibacterial treatment after baseline culture was obtained and before the first dose of study drug; had test-of-cure assessment of cure or failure, but not indeterminate; treatment regimen remained blinded throughout the study duration.

The microbiological modified intent-to-treat (m-mITT) population included c-mITT subjects for whom one or more potentially causative baseline pathogens were identified. The ME population included CE subjects who met the following criteria: had a culture taken from the infection site at baseline that identified one or more potentially causative
pathogen(s) and the primary pathogen was susceptible to both study drugs (ie, tigecycline and either vancomycin or aztreonam); had clinical outcome and microbiologic information available to allow classification of a microbiologic response of eradication, persistence, or superinfection at the test-of-cure assessment.

Outcome Parameters²⁵

The data for evaluable patients were analyzed in terms of the patient’s clinical, microbiological, and pathogen response at the test-of-cure assessment. Clinical efficacy results were communicated as either cure or failure. Microbiological and pathogen responses were reported in terms of eradication, persistence, superinfection, or indeterminate response.

Statistical Analysis²⁵

The use of a noninferiority trial design is standard in phase 3 registration studies of antimicrobial agents. For the cSSSI and cIAI indications, a noninferiority margin of –15% was selected as a balance between the severity of the diseases under study and practical considerations regarding study enrollment. In fact, in each study, the lower bound of the
2-sided 95% confidence interval in both the evaluable and relevant ITT populations was above or near –10%. Furthermore, the 2 studies within each indication were virtually identical to allow for pooling. The final pooled data resulted in a lower bound well above –10% for each indication.

For all of the subpopulation analyses (eg, subgroup analyses, monomicrobial vs polymicrobial infection), an adjusted difference between treatment groups with its 95% confidence interval was calculated from a generalized linear model with a binomial probability function and an identity link (Proc GENMOD). For end points involving comparisons with small sample sizes, the method of Wilson corrected for continuity was used.

Duration of hospitalization, time to defervescence, duration of antibiotic therapy, duration of ICU stay, duration of home care, number of emergency department visits, and number of major procedures required in the operating room (eg, amputations) were analyzed by using the log-rank test. The median was used to estimate central tendency for each treatment group. The Hodges-Lehmann estimate and the 95% confidence intervals were given for the difference between medians, assuming that group distributions differ only by location.

Demographic and baseline characteristics of study subjects were compared between treatment groups. Characteristics that were continuous variables were compared by using a one-way analysis of variance with treatment as a factor. For categorical variables, the Fisher exact test was used. The difference between treatment groups in the percentage of discontinuations from study drug, both overall and for each primary reason, was evaluated by using a 2-sided Fisher exact test.

Complicated Skin and Skin Structure Infections

Protocols 300 and 305 compared the safety and efficacy of tigecycline with vancomycin + aztreonam in patients with cSSSI. Subjects were randomly assigned (in a 1:1 ratio) to receive either tigecycline (an initial 100-mg dose, followed by 50 mg every 12 hours) or vancomycin with aztreonam (1 g vancomycin plus 2 g aztreonam, every 12 hours) via IV administration for up to 14 days. The patients enrolled in the trials were followed up until the test-of-cure visit up to day 90. Subjects were treated intravenously for up to 14 days (minimum, 5 days) of study drug administration, and, unless the subject was a clinical failure, a test-of-cure visit was performed 12 to 92 days after the final dose of study drug. The coprimary efficacy analyses were the clinical response rates for the CE and c-mITT subjects at the test-of-cure assessment.²⁵

Inclusion/Exclusion Criteria, General

Men or women who were 18 years of age or older were eligible to participate in the study if they were expected to need IV antibiotic therapy for at least 5 days and had a known or suspected diagnosis of cSSSI. The infection had to involve deep soft tissue, or require surgical intervention, or be associated with significant underlying disease that complicated the response to treatment.²⁵ Clinical entities included infected ulcers, burns (<5% body surface area, nonfull-skin thickness), major abscess (not treatable through surgery alone), deep or extensive cellulitis, or infected human or animal bites.²⁵ In addition to the infection, the subject had to have at least 2 of the following clinical indicators of infection: drainage or discharge, fever, erythema, swelling, localized warmth, pain/tenderness to palpation, and white blood cell count >10,000/mm³. The subject could not have received more than 2 doses of nonstudy antibacterial therapy after the original culture was obtained. For subjects who were considered prior antibiotic failures, a Gram stain or culture of the baseline infected site showing a potential pathogen was obtained before the first dose of study drug was administered.²⁵

Subjects were excluded if they had a severely impaired arterial blood supply and insufficiency such that amputation of the infected anatomic site was likely within 1 month; infected diabetic foot ulcers or decubitus ulcers where the infection was present for longer than 1 week or chronically infected ulcers in subjects who could not be compliant with measures necessary for chronic wound healing; necrotizing fasciitis or gangrene; any uncomplicated skin and/or skin structure infection; suspected or known infection with P. aeruginosa; clinical suspicion of ecthyma gangrenosum; osteomyelitis contiguous to the infected site; crepitant cellulitis (gas gangrene); or presence of neutropenia, hepatic disease, or creatinine clearance <30 mL/min.²⁵

Efficacy Results

Demographics/Baseline Characteristics

Study 300 was conducted in 8 countries, and study 305 was conducted in 21 countries.²⁵ Demographic and baseline disease characteristics (Table 1) were similar between the treatment groups in each study, with the exception of ethnic origin. In study 300, 53% of the subjects were white and 38% were of other ethnic origin (primarily Hispanic). More than 80% of the subjects in study 305 were white. Approximately 7% of the subjects were 75 years or older.²⁵

Table 1. Demographic and Baseline Characteristics of the CE Population²⁵

	Tigecycline (n=422)	Vancomycin + Aztreonam (n=411)	P  Value
Age, years
Mean	48.36	48.49	0.914
Sex, n (%)			0.830
Male	260 (61.6)	257 (62.5)
Female	162 (38.4)	154 (37.5)
Ethnic origin, n (%)			0.872
White	286 (67.8)	282 (68.6)
Black	33 (7.8)	29 (7.1)
Hispanic	45 (10.7)	44 (10.7)
Asian	15 (3.6)	10 (2.4)
Other	43 (10.2)	46 (11.2)
Weight, kg			0.546
Mean	82.09	81.16
Creatinine clearance, mL/min	109.47	110.07	0.168
N	421	411
Mean	109.08	104.90

Infection type, etiology of disease, and comorbid conditions at baseline were comparable between treatment groups in each study. The most common infections were deep soft tissue infections and major abscess.²⁵ Approximately half of the infections were spontaneous, and approximately 30% were due to trauma. Of note, more subjects had comorbidities in study 300 than in study 305 (diabetes mellitus, 30% versus 13%; injection drug use, 7% versus 0%; and human immunodeficiency virus [HIV] infection, 3% versus 0%, respectively). Fewer than 10% of subjects in either study had peripheral vascular disease (PVD) at baseline. The cSSSI subjects exhibited substantial underlying disease and severity of illness, as indicated by the frequency of diabetes mellitus and major abscesses, respectively.²⁵

Table 2. Clinical Diagnosis of Infections Within the CE Population²⁵

Clinical Diagnosis, n (%)	Tigecycline (n=422)	Vancomycin + Aztreonam (n=411)	Chi-Square P  Value
Any diagnosis			0.937
Deep soft tissue infection	263 (62.3)	259 (63)
Cellulitis*	249 (59)	242 (58.9)
≥10 cm (where anatomically applicable)	226 (53.6)	215 (52.3)
Requiring surgery or drainage	109 (25.8)	119 (29)
Complicated underlying disease	51 (12.1)	67 (16.3)
Wound infection	14 (3.3)	17 (4.1)
Major abscesses	116 (27.5)	116 (28.2)
Infected ulcers	30 (7.1)	23 (5.6)
Burns	9 (2.1)	9 (2.2)
Other	4 (0.9)	4 (1)

*Some subjects with cellulitis met more than one diagnostic criterion.

Results

A favorable clinical response was observed in 165/199 CE subjects in the tigecycline group (82.9%) and 163/198 subjects in the vancomycin + aztreonam group (82.3%) in study 300. Similarly, a favorable clinical response was observed in 209/277 c-mITT subjects in the tigecycline group (75.5%) and 200/260 subjects in the vancomycin + aztreonam group (76.9%). Between-group differences among the CE and c-mITT subjects were not found to be statistically significant.²⁵

A favorable clinical response was observed in 200/223 CE subjects in the tigecycline group (90%) and 201/213 subjects in the vancomycin + aztreonam group (94%) in study 305. Similarly, a favorable clinical response was observed in 220/261 c-mITT subjects in the tigecycline group (84%) and 225/259 subjects in the vancomycin + aztreonam group (87%). Between-group differences in terms of clinical response among the CE and c-mITT subjects were not found to be statistically significant.²⁵

A favorable microbiological response was observed in 139/164 ME subjects in the tigecycline group (85%) and 138/148 subjects in the vancomycin + aztreonam group (93%) in study 305. Between-group differences in terms of microbiological response among ME subjects were found to be statistically significant. A favorable microbiological response was also observed in 166/209 m-mITT subjects in the tigecycline group (79%) and 171/203 subjects in the vancomycin + aztreonam group (84%). Between-group differences in terms of microbiological response among the
m-mITT subjects were not found to be statistically significant.²⁵

Results of the pooled data for studies 300 and 305 showed a favorable clinical response in 365/422 CE subjects in the tigecycline group (86.5%) and 364/411 subjects in the vancomycin + aztreonam group (88.6%) (see Figure 1). Similarly, a favorable clinical response was observed in 429/538 c-mITT subjects in the tigecycline group (79.7%) and 425/519 subjects in the vancomycin + aztreonam group (81.9%). Between-group differences among the CE and
c-mITT subjects were not found to be statistically significant.²⁵

Figure 1. Clinical Cure Rates in cSSSI at Study End in the CE and c-mITT Populations²⁵

P < 0.001 for noninferiority of tigecycline vs vancomycin + aztreonam for each population comparison.
CE = clinically evaluable; c-mITT = clinical modified intent-to-treat.

Figure 2 summarizes clinical responses within the pooled CE population by major clinical diagnosis: deep soft tissue infections, abscesses, ulcers, and burns. Cure rates were high for all categories of clinical diagnoses; however, the adjusted difference could not be calculated due to small cell sizes or other convergence problems. Table 3 summarizes clinical cure rates by comorbid condition within the pooled CE population.

Figure 2. Clinical Cure Rates by Clinical Diagnosis in cSSSI at Study End in the CE Population²⁵

Table 3. Clinical Cure Rates by Comorbid Condition in cSSSI at Study End in the CE Population²⁵

	Tigecycline		Vancomycin + Aztreonam
	n	%	n	%
Diabetes	60/83	72.3	65/85	76.5
Peripheral vascular disease	22/29	75.9	21/28	75.0
Concomitant baseline bacteremia	19/23	82.6	21/24	87.5

Figure 3 presents pooled clinical cure rates at the test-of-cure visit for selected baseline isolates of particular clinical interest in treating cSSSI: MRSA, methicillin-susceptible S. aureus, S. pyogenes, S. agalactiae, E. faecalis, E. coli, and B. fragilis. S. anginosus was also included as a selected baseline isolate of clinical interest because of the role of this isolate in the clinical disease state and the frequency with which it occurred in the pooled data.²⁵

Figure 3. Clinical Cure Rates by Pathogen in cSSSI in the ME Population²⁵

*S. anginosus category includes S. anginosus, S. intermedius, and S. constellatus.
MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-susceptible Staphylococcus aureus;
VSE = vancomycin-susceptible enterococci.

At the ME subject level, 1 of 3 microbiological responses was possible: eradication, persistence, or superinfection. Pooled microbiological responses are presented for the ME and m-mITT populations in Figure 4 for the test-of-cure assessments. The integrated analysis of microbiological response shows that tigecycline was statistically noninferior to vancomycin + aztreonam in the ME population at the test-of-cure assessment based on the lower bound of the
2-sided 95% confidence interval (95% CI, –10.6, 2.4). Eradication rates were not statistically different between the
2 treatment groups at the test-of-cure assessment. The eradication rate was 82.1% for tigecycline-treated subjects and 86.2% for vancomycin + aztreonam-treated subjects. Tigecycline was also statistically noninferior to vancomycin + aztreonam for the m-mITT population at the test-of-cure assessment based on the lower bound of the 2-sided confidence interval (95% CI, –9.1, 3.2). Eradication rates were not statistically different between the 2 treatment groups at the test-of-cure assessment. The eradication rate was 76.2% for tigecycline-treated subjects and 79.1% for vancomycin + aztreonam-treated subjects.²⁵

Figure 4. cSSSI: Eradication Rates²⁵

P < 0.001 for noninferiority of tigecycline vs vancomycin + aztreonam for each population comparison.
ME = microbiologically evaluable; m-mITT = microbiological modified intent-to-treat.

Figure 5 summarizes microbiological responses at the pooled ME subject level for subjects who had monomicrobial or polymicrobial infections. The figure compares differences in eradication rates between tigecycline-treated and vancomycin + aztreonam-treated subjects, adjusted for type of infection.

Figure 5. cSSSI: Eradication Rates by Monomicrobial/Polymicrobial Infection²⁵

The clinical response of failure in the CE population was analyzed by stepwise logistic regression for the following baseline/demographic factors: treatment group, protocol, age, gender, ethnic origin, geographic region (United States, Canada, Eastern Europe, Western Europe, India, Latin America, other), comorbid conditions (diabetes mellitus, PVD, injection drug use, HIV infection), creatinine clearance, clinical diagnosis (cellulitis, abscess, wound ulcer), type of infection (monomicrobial, polymicrobial), baseline pathogen, and combinations of baseline pathogens.²⁵

Subgroup analyses of clinical response in the CE population were performed on pooled data to evaluate the consistency of tigecycline cure rates and the noninferiority of tigecycline to vancomycin + aztreonam. A generalized linear model examined the interaction effects of treatment and the following factors: age, gender, ethnicity, clinical diagnosis, underlying diabetes mellitus and PVD, creatinine clearance, and bacteremia status. No significant interactions with treatment were identified.²⁵

These secondary analyses were not powered sufficiently or designed to statistically show an effect; therefore, these results should be interpreted with caution.

Treatment group was not an independent predictor of failure, supporting the finding of noninferiority in the coprimary analyses. The most consistent independent predictors of failure were diabetes mellitus and geographic region. Subjects who had diabetes at baseline were more likely to have the clinical outcome of failure than subjects who did not have diabetes. This is consistent with the literature that supports diabetes as an important clinical factor in the cure/failure response for patients with cSSSI infections.²⁵ Subjects in Eastern Europe were less likely to have an outcome of failure, and as a result further analysis was completed to assess the differences. These exploratory analyses demonstrated that subjects in Eastern Europe had significantly lower rates of diabetes and fewer MRSA isolated from these infections compared with subjects in other geographic regions.²⁵

The clinical cure rate for tigecycline-treated subjects with bacteremia at baseline in the cSSSI studies was 76.9% (10 of 13).²⁵ The majority of isolated organisms were methicillin-susceptible S. aureus strains.²⁵

Response was also assessed for subjects with cSSSI caused by pathogens with selected genetically defined resistance markers. The presence of tetracycline or methicillin resistance did not affect response. An exploratory analysis, conducted subsequent to completion of the integrated analysis, assessed clinical response in subjects with strains of
S. aureus genotypically characterized as CA-MRSA; note that, at this time, not all MRSA strains in these studies have been analyzed for the presence of CA-MRSA genetic markers, and therefore the results are preliminary. These subjects had a clinical presentation consistent with infection caused by CA-MRSA; all but one strain came from the United States. Clinical response rates were comparable for tigecycline and comparator.²⁵

Conclusions

The results of these studies demonstrated that the clinical efficacy of 50 mg tigecycline, as a single agent infused every 12 hours (after an initial loading dose of 100 mg), is noninferior to the combination antibiotic regimen of 1 g/2 g vancomycin + aztreonam infused every 12 hours in the treatment of subjects with cSSSI.²⁵

Tigecycline met the statistical criteria of noninferiority to the comparative regimen for the primary end points within each of the coprimary populations. Tigecycline met the statistical criteria for noninferiority to comparative regimens in secondary end points, including bacteriological eradication rates in the ME and m-mITT populations. Bacterial susceptibility data indicated that tigecycline is efficacious against isolates commonly observed in subjects with cSSSI. In addition, tigecycline was efficacious against isolates containing genes known to confer antibiotic resistance.²⁵

No significant differences were observed between the treatment groups in the use of inpatient or outpatient health care resources, with the exception of the greater use of concomitant medications to treat nausea/vomiting within the tigecycline group.²⁵

Multiple subpopulation analyses of clinical responses were generally consistent with the findings from the coprimary populations. For each subpopulation analysis, no interaction was observed between treatment and the subpopulation tested.²⁵

Tigecycline is efficacious for the treatment of cSSSI in patient populations broadly representative of those seen in clinical practice. These populations included subgroups that were challenging to treat by virtue of the comorbid conditions as well as characteristics of the infection. Efficacy was also demonstrated in relevant demographic and disease category subgroups.

Tigecycline is indicated for the treatment of adults with complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin–susceptible and –resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.

Results for the cSSSI indication confirm the efficacy of tigecycline against infection caused by organisms with tetracycline resistance determinants.²⁵

Indications

TYGACIL^® (tigecycline) is indicated for the treatment of adults with:

• Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis
• Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus,
  S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros
• Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila

Important Safety Information

• TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline
• Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics
• Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function. Adverse events may occur after the drug has been discontinued
• The safety and efficacy of TYGACIL in patients with hospital-acquired pneumonia have not been established
• TYGACIL may cause fetal harm when administered to a pregnant woman
• The use of TYGACIL during tooth development may cause permanent discoloration of the teeth. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated
• Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis
• Monotherapy should be used with caution in patients with clinically apparent intestinal perforation
• TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL
• To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections proven or strongly suspected to be caused by susceptible bacteria. As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi
• The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT
• Prothrombin time or other suitable anticoagulant test should be monitored if TYGACIL is administered with warfarin
• Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective
• The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established

Please see full Prescribing Information.

Prescribing Information | Pressroom | References | Indications and Important Safety Information