Randomized Phase 2 Trial To Evaluate the Clinical Efficacy of Two High-Dosage Tigecycline Regimens versus Imipenem-Cilastatin for Treatment of Hospital-Acquired Pneumonia

Abstract

cIn a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with tigecycline 100 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%).No new safety signals with the high-dose tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.) H ospital-acquired pneumonia (HAP) remains an important problem in the care of critically ill patients and has significant clinical and economic consequences, including a 30% to 70% mortality rate (1-4). Mortality among patients with HAP associated with mechanical ventilation is approximately twice that of patients with HAP not associated with mechanical ventilation (5). The initial management of patients with HAP includes obtaining appropriate respiratory samples for culture and sensitivity and initiating therapy with broad-spectrum antibiotics that are active against likely pathogens (6).Tigecycline has a broad spectrum of antibacterial activity (7), including activity against many multidrug-resistant organisms and efficacy in treatment of community-acquired pneumonia (8-10). A single-dose study that collected lung tissue from uninfected subjects undergoing elective surgery showed a ratio of lung area under the concentration time-curve (AUC) to serum AUC, which is also known as lung penetration, of 2.0 (11). Results from a multiple-dose study with tigecycline that measured serum, pulmonary epithelial lining fluid (ELF), and alveolar cell concentrations in healthy volunteers demonstrated ELF penetration of 1.32 (12). These results, together with the observation by Crandon e...

Is there a future for tigecycline?

“…A recent phase 2 study in HAP and VAP investigated the use of two high-dosage (HD) tigecycline regimens (200 mg initial, and then 100 mg twice daily or 150 mg initial and then 75 mg twice daily) showing higher cure rates when the ''highest'' HD was used compared to lower dosage and imipenem/cilastatin [16]. The study hypothesized that a higher area under the concentration-time divided by the MIC (AUC/ MIC ratio) above one was necessary on the basis of a previous phase 3 study demonstrating lower cure rates in patients with HAP treated with conventional dose of tigecycline; this effect was attributed to a lower exposure to the drug on the lung tissue level [16]. This undermines the necessity of high doses when the MIC of the pathogen exceeds 0.5 mg/L.…”

“…Furthermore, compared to colistin that did not reach sufficient drug levels in the lung tissue, HD tigecycline was efficacious for treating experimental pneumonia due to metallo-beta-lactamase (NDM-1)-producing Enterobacteriaceae [17]. Although no major issues of toxicity have been displayed at high doses so far, the tolerability of these regimens in large trials still needs to be assessed [16]. Finally, tigecycline's propensity to select for resistant strains (e.g., MDR Acinetobacter spp.)…”

A retrospective observational study of the impact of Tigecycline in treating multidrug resistant pneumonia

“…Ramirez et al compared a higher dose regimen of Tigecycline in a phase two trial for HAP/VAP showing higher clinical efficacy for the higher dose group. 11 But since adequate numbers of patients were not enrolled, the results could not be statistically analysed to be significant. Furthermore, Acinetobacter was not an etiologic agent in the patient group.…”

Sepsis outside intensive care unit: the other side of the coin

“…This is a reassuringly high rate in the light of data obtained in the phase III HAP study of tigecycline versus imipenem that failed to confirm the non-inferiority of tigecycline in the clinically evaluable patient subset. A subsequent phase II study with tigecycline used at higher dosages indicated increased efficacy with a clinical cure rate of 85 % [16]. There are several, at least, theoretical reasons why non-bactericidal antimicrobial agents such as tigecycline are effective in severe infections [17].…”