Safety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results from a double-blind randomized phase 3 comparison study with levofloxacin

171

103

The aim of this study was to compare the efficacy and safety of tigecycline, a newly developed glycylcycline antibiotic, with those of empirical antibiotic regimens which have been reported to possess good efficacy for complicated skin and skin structure infections (cSSSIs), complicated intra-abdominal infections (cIAIs), community-acquired pneumonia (CAP), and other infections caused by methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE CI ‫؍‬ 0.69 to 1.07, P ‫؍‬ 0.19). The incidence of adverse events in the tigecycline group was significantly higher than that in the other therapy groups with a statistical margin (for the modified intent-to-treat [mITT] population, OR ‫؍‬ 1.33, 95% CI ‫؍‬ 1.17 to 1.52, P < 0.0001), especially in the digestive system (mITT population, OR ‫؍‬ 2.41, 95% CI ‫؍‬ 1.67 to 3.46, P < 0.00001). No difference regarding all-cause mortality and drug-related mortality between tigecycline and the other regimens was found, although numerically higher mortality was found in the tigecycline group. This meta-analysis provides evidence that tigecycline monotherapy may be used as effectively as the comparison therapy for cSSSI, cIAIs, CAP, and infections caused by MRSA/VRE. However, because of the high risk of mortality, AEs, and emergence of resistant isolates, prudence with the clinical use of tigecycline monotherapy in infections is required.The threat of antimicrobial resistance has been identified as one of the major challenges facing public health, and antimicrobial resistance has increased rates of morbidity and mortality and socioeconomic costs. The rapid rate of microbial evolution underscores the urgent need for development of new agents that overcome existing mechanisms of resistance displayed by multidrug-resistant bacteria.Tigecycline is a first-in-class expanded-broad-spectrum glycylcycline. It inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit but with a five times higher affinity than that for the tetracyclines (4). In vitro studies demonstrate that it has good activity against many commonly encountered respiratory bacteria, including multiple resistant Gram-positive, Gram-negative, anaerobic, as well as multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin-resistant Enterococcus (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP), and ␤-lactamase-producing Haemophilus influenzae, among others (5). Tigecycline overcomes the two key tetracycline resistance mechanisms (efflux pumps and ribosomal protection) and is unaffected by other bacterial mechanisms of resistance, such as extended-spectrum ␤-lactamases (32).Tigecycline was first approved for use for indications of complicated skin and skin structure infections (cSSSIs) and complicated intra-abdominal infections (cIAIs). Currently, it is approved for use for community-acquired pneumonia (CAP). It has also been found to be effective for the trea...

Section: Resultsmentioning

confidence: 99%

“…Data regarding the success of treatment with the administered antimicrobial regimens for CE and c-mITT patients were reported in seven RCTs (2,3,6,7,35,43,45). The treatment success of one RCT (16) was based on ME and m-mITT populations, so it was not included here.…”

Section: Resultsmentioning

confidence: 99%

Systematic Review and Meta-Analysis of the Effectiveness and Safety of Tigecycline for Treatment of Infectious Disease

Cai

Wang

Liang

et al. 2011

171

103

“…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)(9)(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).…”

mentioning

confidence: 99%

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

Ramirez

Dartois

Gandjini

et al. 2013

206

182

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...

“…When the timing of ECG measurements coincided with blood collection, the ECG measurement was performed prior to blood collection. Blood samples (5 ml) for PK analysis were collected at 0 h (baseline) and 0.5, 1, 2, 3,4,8,12,16,24,48,72, and 96 h postdose. Serum samples were separated by centrifugation after clotting at room temperature, and serum samples were stored at approximately Ϫ20°C within 1 h of collection and assayed within the 617 days of established stability data.…”

Section: Methodsmentioning

confidence: 99%

“…The efficacy and safety of tigecycline for these indications have been demonstrated in phase 3 clinical trials (7)(8)(9)(10)(11)(12). The recommended treatment regimen for tigecycline includes an initial infusion of 100-mg dose followed by 50 mg every 12 h (6), although in practice some clinicians have acknowledged using higher doses (13).…”

mentioning

confidence: 99%

Tigecycline Does Not Prolong Corrected QT Intervals in Healthy Subjects

Korth‐Bradley¹,

McGovern²,

Salageanu³

et al. 2013

We evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (C max ), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC 0 -ؕ ), 2,366 ng · h/ml; clearance ( T igecycline is a broad-spectrum glycylcycline that binds to the 30S ribosomal subunit blocking entry of amino-acyl tRNA and preventing peptide chain elongation. Tigecycline overcomes two major mechanisms of tetracycline resistance, ribosomal protection and efflux; however, resistance via nonspecific multidrug efflux pumps has been demonstrated (1). Its in vitro spectrum of activity includes many Gram-positive and Gram-negative organisms, anaerobes, atypical organisms, and some multidrug-resistant pathogens (2-5). These attributes suggest a role for tigecycline in the empirical treatment of susceptible and resistant pathogens and the definitive treatment of tigecycline-susceptible resistant bacteria.Tigecycline is approved for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community-acquired bacterial pneumonia (6). The efficacy and safety of tigecycline for these indications have been demonstrated in phase 3 clinical trials (7-12). The recommended treatment regimen for tigecycline includes an initial infusion of 100-mg dose followed by 50 mg every 12 h (6), although in practice some clinicians have acknowledged using higher doses (13).In a pooled analysis of phase 3 and 4 studies in patients with a variety of infections, an increase in all-cause mortality was found in tigecycline-treated patients versus comparators. In some other classes of antibiotics, such as macrolides and fluoroquinolones, mortality rates may be adversely affected by prolongation of the cardiac QTc (corrected QT) interval (14,15).Thorough QT studies were not routinely performed at the time of the clinical development of tigecycli...