Establishing the Role of Tigecycline in an era of Antimicrobial Resistance

Jason J. Schafer; Debra A. Goff

Disclosures

Expert Rev Anti Infect Ther. 2008;6(5):557-567. 

In This Article

Clinical Efficacy

Phase I Trials

Single- and multiple-dose studies have investigated the pharmacokinetic profile and tolerability of tigecycline in healthy volunteers.[7,8,43] One study evaluated the influence of age and gender on single-dose tigecycline pharmacokinetics. Although steady-state volume of distribution differed between men and women, no gender- or age-specific dosage adjustments were found to be required.[43]

Three additional Phase I, randomized, double-blind, placebo-controlled trials evaluated the safety and tolerability of tigecycline.[8] Two of these studies also evaluated tigecycline pharmacokinetics at various doses and infusion rates. Although no serious adverse events occurred with tigecycline in these studies, nausea and vomiting were the most common events that occurred and appeared to be dose related. In addition, one study found these adverse events to be diminished in fed patients versus those who had fasted.[8]

Phase II Trials

There have been two Phase II trials investigating tigecycline for the treatment of cSSIs and cIAIs in adult patients.[44,45] The evaluation of tigecycline for treating cSSIs was a randomized, open-label, multicenter study that assessed the efficacy, tolerability, and pharmacokinetic differences of two dosing regimens.[44] Patients received either a 100-mg loading dose followed by 50 mg every 12 h or a 50-mg loading dose followed by 25 mg every 12 h for 7-14 days. Of the 160 patients who received at least one dose of study drug, 112 and 91 were clinically and microbiologically evaluable at a test-of-cure visit, respectively. Clinical cure rate was 67% (37 out of 55) for the 25-mg regimen and 74% (40 out of 54) for the 50-mg regimen. Microbiological response occurred in 56 and 69% for the 25- and 50-mg regimens, respectively. The differences in clinical and microbial responses between groups were not statistically significant. Nausea and vomiting were the most common adverse events reported and occurred irrespective of the dosing regimens administered. Tigecycline was found to be efficacious and well tolerated in adult patients for the treatment of cSSIs.

A multicenter, open-label, Phase II investigation has also been performed for the management of cIAIs requiring surgical intervention.[45] A total of 111 patients were enrolled with complicated infections, including perforated gangrenous appendicitis, cholecystitis or perforated diverticulitis and peritonitis. Each patient received intravenous tigecycline administered as a 100-mg loading dose followed by 50 mg every 12 h for 5-14 days. The inclusion criteria were satisfied for 66 patients. Clinical cure rate was evaluated at test-of-cure and end-of-treatment visits and was 67 and 76%, respectively. Furthermore an intent-to-treat analysis showed test-of-cure and end-of-treatment clinical cure rates of 55 and 72%, respectively. Again, nausea and vomiting were found to be the most common adverse events reported. The authors determined that tigecycline was safe and effective for managing cIAIs in hospitalized patients.

Phase III Trials

Complicated Intra-abdominal Infections. Two Phase III, double-blind, randomized controlled trials have evaluated the safety and efficacy of tigecycline versus imipenem-cilastatin in a total of 1642 adult patients with cIAIs. These trials are similar in study design and have been described in a pooled analysis.[46] Enrolled patients included those requiring a surgical intervention for the management of a cIAI defined by the following: postsurgical intra-abdominal abscess; appendicitis complicated by perforation and/or a peri-appendiceal abscess; perforated diverticulitis; complicated cholecystitis with evidence of perforation, empyema or gangrene; perforation of a gastric or duodenal ulcer; purulent peritonitis or peritonitis associated with fecal contamination; or perforation of the large or small intestine with abscess or fecal contamination.

Patients were randomized to receive either a tigecycline 100-mg loading dose followed by 50 mg every 12 h or imipenem-cilastatin adjusted for renal function for 5-14 days. The severity of illness was defined using acute physiology and chronic health evaluation II (APACHE II) calculations and was similar between treatment groups (6.3 for tigecycline and 6.0 for imipenem). The primary end point was clinical cure in the microbiologically evaluable or modified intent-to-treat groups at a test-of-cure visit (12-42 days after therapy).

The most common cIAI encountered was complicated appendicitis (50%), followed by complicated cholecystitis (17%). Overall, rates of clinical cure between agents were similar for microbiologically evaluable groups (86.1% [95% confidence interval {CI}: 82.2-89.0] for tigecycline and 86.2% [95% CI: 82.9-89.0] for imipenem) and modified intent-to-treat groups (80.2% [95% CI: 76.9-83.2] for tigecycline and 81.5% [95% CI: 78.2-84.4] for imipenem). In addition, similar rates of clinical cure were observed in patients receiving tigecycline or imipenem-cilastatin with monomicrobial or polymicrobial infections. The authors concluded that tigecycline monotherapy is effective, well tolerated and comparable to imipenem-cilastatin for treating cIAIs.

Complicated Skin and Skin-structure Infections. The safety and efficacy of tigecycline has been compared with vancomycin plus aztreonam for the management of cSSIs in two randomized, double-blind, controlled trials. The results of these trials have been included in a pooled analysis.[47]

Patients eligible for study inclusion were hospitalized adults who received a minimum of 5 days of antibiotic therapy for cSSIs that met the following criteria: involvement of deep soft tissue, including cellulitis of at least 10 cm in width or length; those requiring surgical intervention; or infections associated with significant underlying disease (e.g., diabetes mellitus, peripheral vascular disease, peripheral neuropathy or lower venous insufficiency). Inclusion was also reliant upon the presence of at least two of the following signs and symptoms: drainage or discharge, fever, erythema, swelling, localized warmth, pain and/or white blood cell count higher than 10,000 cells/mm3.

Study patients were randomized to receive either tigecycline (100 mg loading dose followed by 50 mg twice daily) or vancomycin (1 g twice daily) plus aztreonam (2 g twice daily) for up to 14 days. The primary end point evaluated at a test-of-cure visit (12-92 days after the last antibiotic dose) was clinical response within the clinically evaluable and modified intent-to-treat groups.

Deep soft-tissue infection involving cellulitis (59%) was the most common diagnosis in both groups, many of which required surgical intervention. MSSA was the most commonly isolated pathogen. Again, a similar rate of clinical cure between the study drug and its comparators was demonstrated for the clinically evaluable (86.5% [95% CI: 82.9-89.6] for tigecycline and 88.6% [95% CI: 85.1-91.5] for vancomycin/aztreonam) and modified intent-to-treat populations (79.7% [95% CI: 76.1-83.1] for tigecycline and 81.9% [95% CI: 78.3-85.1] for vancomycin/aztreonam). Additionally, overall microbial eradication for patients infected with MRSA was nearly identical among treatment groups (78.1% [95% CI: 60.0-90.7] for tigecycline and 75.8% [95% CI: 57.7-88.9] for vancomycin/aztreoanam). The authors concluded that tigecycline was well tolerated and as effective as vancomycin plus aztreonam for the treatment of cSSIs.

Community-acquired Pneumonia. Two randomized, multicenter, double-blind Phase III clinical trials have evaluated the safety and efficacy of tigecycline in comparison to levofloxacin for the management of hospitalized patients with community-acquired pneumonia (CAP).[48] Included patients were stratified by a Fine Pneumonia Severity Index score and were randomized to receive either tigecycline (100-mg loading dose followed by 50 mg every 12 h) or intravenous levofloxacin (500 mg daily in one trial and daily or twice daily in the second trial). In addition, one of the two trials allowed for a change to oral levofloxacin after 3 days of either study medication. The primary study end points evaluated at a test-of-cure visit, were clinical response in the clinically evaluable and modified intent-to -treat groups. Secondary end points evaluated were microbiologic efficacy and susceptibility of CAP bacteria to tigecycline. As a baseline assessment, respiratory tract specimens (including sputum cultures), blood cultures, serology, and Legionella and pneumococcal urinary antigens were obtained where possible.

Criteria for study inclusion were as follows:

  • Adult patients hospitalized with CAP severe enough to receive intravenous antibiotics;

  • Fever within 24 h;

  • Chest radiograph indicating a new infiltrate within 48 h of the first dose of medication;

The presence of at least two of the following signs and symptoms: cough; purulent sputum; a change in sputum consistent with infection; rales on auscultation and/or the presence of consolidation; dyspnea or tachypnea; elevated white blood cell counts of greater than 10,000 cells/mm3 and hypoxemia.

Subjects were excluded if they had been hospitalized within the last 14 days or had resided in a long-term care facility for at least 14 days before symptom onset. Other exclusions included patients requiring ICU treatment at randomization, known or suspected P. aeruginosa infection, active TB or known Legionella pneumonia.

A total of 846 patients were randomized and received at least one dose of study medication. The majority of these patients (tigecycline 80.7% and levofloxacin 74.4%) and nearly half (tigecycline 46.5% and levofloxacin 47.2%) had a Fine Pneumonia Severity Index score of II-IV and III-V, respectively.

There were no significant differences in the rate of clinical cure between tigecycline and levofloxacin for the clinically evaluable (89.7 and 86.3%, respectively) and modified intent-to-treat groups (81 and 79.7%, respectively). Similar rates of clinical cure were also found in patients with bacteremia (90.9% [95% CI: 70.8-98.9] for tigecycline and 72.2% [95% CI: 46.5-90.3] for levofloxacin) and patients over 65 years (88.0% [95% CI: 79.0-94.1] for tigecycline and 81.9% [95% CI: 72.6-89.1] for levofloxacin). No differences in clinical cure were identified between treatment groups with regard to baseline respiratory pathogens, including patients with penicillin-intermediate and -resistant S. pneumoniae (n = 10 and n = 9, respectively). The development of resistance to study drugs was not observed during therapy.

In addition to clinical cure and microbiologic efficacy, investigators also found similar outcomes between treatment groups with respect to hospital length of stay (tigecycline: mean [standard deviation] = 9.8 [6.0] days; levofloxacin = 9.8 [6.0] days); duration of antibiotic therapy (tigecycline = 9.8 [3.1]; levofloxacin = 10.0 [3.2] days) and rate of re-hospitalization following discharge. The authors concluded that tigecycline monotherapy is well tolerated and as efficacious as levofloxacin for the treatment of hospitalized patients with CAP.

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