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TYGACIL® (tigecycline) Clinical Studies

14 CLINICAL STUDIES

14.1 Complicated Skin and Skin Structure Infections

TYGACIL was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 4. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 5.

Table 4. Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after 5 to 14 Days of Therapy
TYGACIL*
n/N (%)
Vancomycin/Aztreonam
n/N (%)
*
100 mg initially, followed by 50 mg every 12 hours
Vancomycin (1 g every 12 hours)/Aztreonam (2 g every 12 hours)
Study 1
  CE 165/199 (82.9) 163/198 (82.3)
  c-mITT 209/277 (75.5) 200/260 (76.9)
Study 2
  CE 200/223 (89.7) 201/213 (94.4)
  c-mITT 220/261 (84.3) 225/259 (86.9)
Table 5. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure Infections*
Pathogen TYGACIL
n/N (%)
Vancomycin/Aztreonam
n/N (%)
*
Two cSSSI pivotal studies and two Resistant Pathogen studies
Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus
Escherichia coli 29/36 (80.6) 26/30 (86.7)
Enterobacter cloacae 10/12 (83.3) 15/15 (100)
Enterococcus faecalis (vancomycin-susceptible only) 15/21 (71.4) 19/24 (79.2)
Klebsiella pneumoniae 12/14 (85.7) 15/16 (93.8)
Methicillin-susceptible Staphylococcus aureus (MSSA) 124/137 (90.5) 113/120 (94.2)
Methicillin-resistant Staphylococcus aureus (MRSA) 79/95 (83.2) 46/57 (80.7)
Streptococcus agalactiae 8/8 (100) 11/14 (78.6)
Streptococcus anginosus grp. 17/21 (81.0) 9/10 (90.0)
Streptococcus pyogenes 31/32 (96.9) 24/27 (88.9)
Bacteroides fragilis 7/9 (77.8) 4/5 (80.0)

14.2 Complicated Intra-abdominal Infections

TYGACIL was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.

Table 6. Clinical Cure Rates from Two Studies in Complicated Intra-abdominal Infections after 5 to 14 Days of Therapy
TYGACIL*
n/N (%)
Imipenem/Cilastatin
n/N (%)
*
100 mg initially, followed by 50 mg every 12 hours
Imipenem/Cilastatin (500 mg every 6 hours)
Study 1
  ME 199/247 (80.6) 210/255 (82.4)
  m-mITT 227/309 (73.5) 244/312 (78.2)
Study 2
  ME 242/265 (91.3) 232/258 (89.9)
  m-mITT 279/322 (86.6) 270/319 (84.6)
Table 7. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal Infections*
Pathogen TYGACIL
n/N (%)
Imipenem/Cilastatin
n/N (%)
*
Two cIAI pivotal studies and two Resistant Pathogen studies
Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus
Citrobacter freundii 12/16 (75.0) 3/4 (75.0)
Enterobacter cloacae 15/17 (88.2) 16/17 (94.1)
Escherichia coli 284/336 (84.5) 297/342 (86.8)
Klebsiella oxytoca 19/20 (95.0) 17/19 (89.5)
Klebsiella pneumoniae 42/47 (89.4) 46/53 (86.8)
Enterococcus faecalis 29/38 (76.3) 35/47 (74.5)
Methicillin-susceptible Staphylococcus aureus (MSSA) 26/28 (92.9) 22/24 (91.7)
Methicillin-resistant Staphylococcus aureus (MRSA) 16/18 (88.9) 1/3 (33.3)
Streptococcus anginosus grp. 101/119 (84.9) 60/79 (75.9)
Bacteroides fragilis 68/88 (77.3) 59/73 (80.8)
Bacteroides thetaiotaomicron 36/41 (87.8) 31/36 (86.1)
Bacteroides uniformis 12/17 (70.6) 14/16 (87.5)
Bacteroides vulgatus 14/16 (87.5) 4/6 (66.7)
Clostridium perfringens 18/19 (94.7) 20/22 (90.9)
Peptostreptococcus micros 13/17 (76.5) 8/11 (72.7)

14.3 Community-Acquired Bacterial Pneumonia

TYGACIL was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In Study 1, after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.

Table 8. Clinical Cure Rates from Two Studies in Community-Acquired Bacterial Pneumonia after 7 to 14 Days of Total Therapy
TYGACIL*
n/N (%)
Levofloxacin
n/N (%)
95% CI
*
100 mg initially, followed by 50 mg every 12 hours
Levofloxacin (500 mg intravenous every 12 or 24 hours)
95% confidence interval for the treatment difference
§
After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 1.
Study 1§
  CE 125/138 (90.6) 136/156 (87.2) (-4.4, 11.2)
  c-mITT 149/191 (78) 158/203 (77.8) (-8.5, 8.9)
Study 2
  CE 128/144 (88.9) 116/136 (85.3) (-5.0, 12.2)
  c-mITT 170/203 (83.7) 163/200 (81.5) (-5.6, 10.1)
Table 9. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial Pneumonia*
Pathogen TYGACIL
n/N (%)
Levofloxacin
n/N
(%)
*
Two CABP studies
Includes cases of concurrent bacteremia [cure rates of 20/22 (90.9%) versus 13/18 (72.2%) for TYGACIL and levofloxacin respectively]
Haemophilus influenzae 14/17 (82.4) 13/16 (81.3)
Legionella pneumophila 10/10 (100.0) 6/6 (100.0)
Streptococcus pneumoniae (penicillin-susceptible only) 44/46 (95.7) 39/44 (88.6)

To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibacterial drugs is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:

  • Age ≥50 years
  • PSI score ≥3
  • Streptococcus pneumoniae bacteremia

The results of this analysis are shown in Table 10. Age ≥50 was the most common risk factor in the higher-risk group.

Table 10. Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of Mortality*
TYGACIL
n/N (%)
Levofloxacin
n/N
(%)
95% CI
*
Patients at higher risk of death include patients with any one of the following: ≥50 year of age; PSI score ≥3; or bacteremia due to Streptococcus pneumoniae
95% confidence interval for the treatment difference
After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 1.
Study 1
  CE
  Higher risk
    Yes 93/103 (90.3) 84/102 (82.4) (-2.3, 18.2)
    No 32/35 (91.4) 52/54 (96.3) (-20.8, 7.1)
  c-mITT
  Higher risk
    Yes 111/142 (78.2) 100/134 (74.6) (-6.9, 14)
    No 38/49 (77.6) 58/69 (84.1) (-22.8, 8.7)
Study 2
  CE
  Higher risk
    Yes 95/107 (88.8) 68/85 (80) (-2.2, 20.3)
    No 33/37 (89.2) 48/51 (94.1) (-21.1, 8.6)
  c-mITT
  Higher risk
    Yes 112/134 (83.6) 93/120 (77.5) (-4.2, 16.4)
    No 58/69 (84.1) 70/80 (87.5) (-16.2, 8.8)

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