• Studies 308 and 313 were both phase 3, multicenter, double-blind, randomized studies comparing the safety and clinical efficacy of tigecycline with levofloxacin in hospitalized subjects with community-acquired bacterial pneumonia (CABP).²⁸
• Patients were stratified at randomization by the Fine Pneumonia Severity Index score (Fine NEJM 1997) (Fine score = V, IV, 3, or < than 3 in Study 313 and Fine score = IV or <IV in Study 308) and/or geographic region (Study 308) and randomly assigned (in a 1:1 ratio) to receive either tigecycline or levofloxacin via intravenous (IV) administration.²⁸
• Treatment regimens consisted of either: tigecycline, 100 mg IV followed by subsequent 50 mg doses every
  12 hours; versus, levofloxacin, 500 mg administered IV once daily or twice daily (Study 313 only) for at least
  7 days.²⁸
• In Study 308, patients in both arms were required to be in the hospital for a minimum of 3 days (or receive 6 doses of double-blind IV study medication) with the option to be switched to oral, open-label, levofloxacin after >3 days of IV treatment, in patients demonstrating clinical improvement (improvement in signs and symptoms of pneumonia, afebrile for at least 24 hours, white blood cell count improving, and adequate oral intake).²⁸
• In both studies, total duration of study therapy was 7 to 14 days.
• To be evaluable, the test-of-cure (TOC) assessment had to occur between 7 and 23 days following the last dose of study medication.²⁸

Inclusion/Exclusion Criteria

Both men and women over 18 years of age qualified for participation in these studies if:

• They were hospitalized with CABP and required IV antibiotic therapy.
• Manifested fever or hypothermia and at least two of the following:
• Cough, production of purulent sputum or change in character of sputum consistent with bacterial infection, auscultatory findings consistent with pulmonary consolidation, dyspnea or tachypnea, elevated peripheral WBC count (>10x10⁹/L), or >15% immature neutrophils, leukopenia (<4.5x10⁹/L), hypoxemia
  (PO₂<60 mm Hg or oxygen saturation <90% while on room air).
• Chest radiography showing a new infiltrate within 48 hours of the first dose of test article.²⁸

Patients were excluded if:

• They had received more than 1 dose of a non-study antibacterial agent (single agent or combination therapy) with a dose administration interval less than once daily to treat the current episode of CABP before the first dose of the study drug was administered, with the exception of those patients who failed to respond to a previous course of outpatient oral antibiotic treatment for the same CABP episode.
• Hospitalization in the preceding 14 days
• Residing in a long-term care facility for ≥14 days prior to onset of symptoms
• Requiring ICU treatment at the time of randomization
• Known or suspected Pseudomonas aeruginosa infection
• Active tuberculosis
• Known Legionella pneumophila infection²⁸

Results

Demographics/Baseline Characteristics

The primary end points examined in these studies were the clinical responses in the CE and c-mITT populations at the TOC visit.²⁸ A total of 574 subjects from the combined study populations were considered clinically evaluable, 282 treated with tigecycline and 292 treated with levofloxacin. These two groups were not significantly different with regards to age, sex, weight, creatinine clearance, FINE pneumonia severity index, CURB-65 score, or other comorbid conditions.²⁸

Clinical Efficacy, Individual Studies

Study 308 was conducted in 54 sites across North, Central, and South America.²⁸ The primary efficacy end point was the clinical response at the test of cure (TOC) visit in the co-primary populations of the CE and c-mITT patients. In the CE population following 7 to 14 days of treatment, tigecycline-treated subjects experienced a cure rate of 125/138 (90.6%) while levofloxacin-treated subjects experienced a cure rate of 136/156 (87.2%) (USPI 2009). In the c-mITT groups, response rates were also comparable, 149/191 (78.0%) in the tigecycline-treated arm compared to 158/203 (77.8%) in the levofloxacin group (USPI 2009).¹

Study 313 was conducted in 62 sites across Europe, Africa, and the Asia Pacific region.²⁸ Similar to Study 308, there was no significant difference in the Clinical Response rate of the CE population at the TOC assessment between the two test articles. The clinical cure rates in the CE population following 7 to 14 days of therapy for the two treatment arms were 128/144 (88.9%) for tigecycline and 116/136 (85.3%) for levofloxacin. The clinical sure rates in the c-mITT populations following 7 to 14 days of therapy were 170/203 (83.7%) for tigecycline and 163/200 (81.5%) for levofloxacin (USPI 2009).¹ The microbiological eradication rates for ME subjects who received tigecycline were comparable with those who received levofloxacin for both Studies 308 and 313.

Clinical Efficacy, Pooled Data

The primary end points examined in these studies were the clinical responses in the CE and c-mITT populations at the TOC visit. There were no significant differences in the clinical cure rates between the two treatment groups at the TOC assessment in either population (CE, and c-mITT). The cure arte for the CE population receiving tigecycline was 253/282 (89.7%) compared to 252/292 (86.3%) for levofloxacin, satisfying the criteria for noninferiority (absolute difference [tigecycline-levofloxacin] = 3.4%; 95% CI = [-2.2, 9.1], test for non-inferiority P<.001). Similarly, in the c-mITT groups, 319/394 (81.0%) of tigecycline subjects were considered "cured" while 321/403 (79.7%) of levofloxacin subjects were "cured" (absolute difference [tigecycline-levofloxacin] = 1.3%; 95% CI = [-4.5, 7.1] test for non-inferiority P <.001).²⁸

Many secondary and exploratory analyses were conducted to understand the efficacy of tigecycline in special populations and clinical situations. First, within the m-mITT populations, the tigecycline-treated subjects experienced a cure rate of 192/25 (85.3%) versus 194/232 (83.6%) in those treated with levofloxacin.²⁵ In the ME populations, response rates at the TOC visit were 152/166 (91.6%) for tigecycline versus 160/179 (89.4%) for levofloxacin. These results statistically supported non-inferiority between the treatment groups (P <.001).²⁵

With regard to clinical indicators of disease of severity, no significant difference in cure rates were detected following stratification of subjects by Fine severity score.²⁵ No significant difference in clinical response was detected between the treatment groups in patients with unilobar or multilobar disease.²⁵

A similar finding on nonsignificant difference was described for patients based on the presence or absence of pleural effusions.²⁵

Microbiologic responses were categorized as eradication, persistence, indeterminate, or superinfection. In the ME populations at the TOC assessment, eradication rates did not differ between treatment groups (152/166 or 91.6% for tigecycline versus 161/179 or 89.9% for levofloxacin).²⁵ A similar result was found for the m-mITT groups, with eradication rates assessed at 193/225 or 85.5% for tigecycline and 195/232 or 84.1% for levofloxacin.²⁵ Microbiologic responses in the ME and m-mITT populations were further characterized at the pathogen level. Results-specific PISP and PRSP isolates are presented in the section discussing "Resistant Pathogens." No subjects diagnosed with CABP secondary to MRSA were enrolled in this study.

No differences between therapeutic groups were found when examined based upon detection of bacteremia.²⁸

Among other secondary analyses, comparison of clinical cure and microbiological eradication rates in subjects with monomicrobial versus polymicrobial infections were also consistent with the finding of noninferiority between tigecycline and levofloxacin. Among monomicrobial infections, the cure rate in the ME population for patients receiving tigecycline was 92.1% (105/114) compared to 90.0% (117/130) for levofloxacin.²⁵ Similarly, in subjects with polymicrobial infections, the cure rates for tigecycline and levofloxacin were 91.3% (42/46) and 89.4% (42/47), respectively.²⁵ Similar results were obtained following analysis of the m-mITT population.

Finally, a variety of clinically important health outcomes were examined as secondary and exploratory analyses in these studies. No statistically significant differences between subjects receiving tigecycline and levofloxacin were detected when stratified by overall length of stay²⁸, overall mortality²⁵, time to defervescence²⁵, mean duration of antibiotic therapy²⁸, proportion of patients switched to oral therapy²⁸, and duration of oral therapy post-treatment²⁸. Tigecycline was associated with a lower proportion of subjects requiring concomitant antibiotic treatment (tigecycline= 5.6% versus levofloxacin= 11.7%, P<0.002).²⁸

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
• An increase in all-cause mortality has been observed across phase 3 and 4 clinical studies in TYGACIL-treated patients versus comparator-treated patients. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options
• 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
• Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis
• 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.