RESUMEN
Exposure-response analyses for efficacy and safety were performed for tigecycline-treated patients suffering from community-acquired pneumonia. Data were collected from two randomized, controlled clinical trials in which patients were administered a 100-mg loading dose followed by 50 mg of tigecycline every 12 h. A categorical endpoint, success or failure, 7 to 23 days after the end of therapy (test of cure) and a continuous endpoint, time to fever resolution, were evaluated for exposure-response analyses for efficacy. Nausea/vomiting, diarrhea, headache, and changes in blood urea nitrogen concentration (BUN) and total bilirubin were evaluated for exposure-response analyses for safety. For efficacy, ratios of the free-drug area under the concentration-time curve at 24 h to the MIC of the pathogen (fAUC(0-24):MIC) of ≥12.8 were associated with a faster time to fever resolution; patients with lower drug exposures had a slower time to fever resolution (P = 0.05). For safety, a multivariable logistic regression model demonstrated that a tigecycline AUC above a threshold of 6.87 mg · hr/liter (P = 0.004) and female sex were predictive of the occurrence of nausea and/or vomiting (P = 0.004). Although statistically significant, the linear relationship between tigecycline exposure and maximum change from baseline in total bilirubin is unlikely to be clinically significant.
Asunto(s)
Antibacterianos/farmacología , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Minociclina/análogos & derivados , Neumonía Bacteriana/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/sangre , Antibacterianos/farmacocinética , Área Bajo la Curva , Bilirrubina/sangre , Nitrógeno de la Urea Sanguínea , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/microbiología , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Minociclina/sangre , Minociclina/farmacocinética , Minociclina/farmacología , Neumonía Bacteriana/sangre , Neumonía Bacteriana/microbiología , Análisis de Regresión , Factores Sexuales , Streptococcus pneumoniae/crecimiento & desarrollo , Tigeciclina , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Switch therapy is a management approach combining early discontinuation of intravenous (IV) antibiotics, switch to oral antibiotics, and early hospital discharge. This analysis compares switch therapy using tigecycline versus levofloxacin in hospitalized patients with community-acquired pneumonia (CAP). METHODS: A prospective, randomized, double-blind, Phase 3 clinical trial; patients were randomized to IV tigecycline (100 mg, then 50 mg q12h) or IV levofloxacin (500 mg q24h). Objective criteria were used to define time to switch therapy; patients were switched to oral levofloxacin after ≥6 IV doses if criteria met. Switch therapy outcomes were assessed within the clinically evaluable (CE) population. RESULTS: In the CE population, 138 patients were treated with IV tigecycline and 156 were treated with IV levofloxacin. The proportion of the population that met switch therapy criteria was 67.4% (93/138) for tigecycline and 66.7% (104/156) for levofloxacin. The proportion that actually switched to oral therapy was 89.9% (124/138) for tigecycline and 87.8% (137/156) for levofloxacin. Median time to actual switch therapy was 5.0 days each for tigecycline and levofloxacin. Clinical cure rates for patients who switched were 96.8% for tigecycline and 95.6% for levofloxacin. Corresponding cure rates for those that met switch criteria were 95.7% for tigecycline and 92.3% for levofloxacin. CONCLUSIONS: Switch therapy outcomes in hospitalized patients with CAP receiving initial IV therapy with tigecycline are comparable to those of patients receiving initial IV therapy with levofloxacin. These data support the use of IV tigecycline in hospitalized patients with CAP when the switch therapy approach is considered. CLINICALTRIALS.GOV IDENTIFIER: NCT00081575.
Asunto(s)
Antibacterianos/administración & dosificación , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Levofloxacino , Minociclina/análogos & derivados , Ofloxacino/administración & dosificación , Neumonía Bacteriana/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Minociclina/administración & dosificación , Estudios Prospectivos , Tigeciclina , Resultado del TratamientoRESUMEN
BACKGROUND: Tigecycline is effective in the treatment of complicated skin/skin-structure infection (cSSSI), complicated intraabdominal infection (cIAI), and community-acquired bacterial pneumonia (CAP), but its efficacy in subjects with secondary bacteremia is unknown. METHODS: Pooled data from subjects enrolled for treatment of cSSSI, cIAI, or CAP presenting with bacteremia from 7 double-blind and 1 open-label trial of tigecycline compared with vancomycin-aztreonam, imipenem-cilastatin, levofloxacin, vancomycin, or linezolid were analyzed. The primary efficacy end point was the clinical cure rate at the test-of-cure assessment. RESULTS: A total of 170 subjects were identified (91 tigecycline recipients and 79 recipients of the comparator agent). Clinical cure rates were 81.3% and 78.5% for tigecycline and the comparator, respectively (P = .702). Analysis by sex, age, creatinine clearance, infection site, Acute Physiology and Chronic Health Evaluation score, and Fine score demonstrated no significant between-group differences. Clinical cure rates for the most commonly represented pathogens (Staphylococcus aureus, Streptococcus pneumoniae, and gram-negative species) were also not significantly different between treatment groups. No decrease in the rate of cure was found in organisms with increasing tigecycline minimum inhibitory concentrations. Nine subjects treated with tigecycline and 1 subject treated with comparator were found to have persistent bacteremia. No clinically significant differences in safety parameters were identified. CONCLUSIONS: Tigecycline was generally safe and well tolerated in the treatment of secondary bacteremia associated with cSSSI, cIAI, and CAP; cure rates were similar to comparative standard therapies.
Asunto(s)
Antibacterianos/administración & dosificación , Bacteriemia/tratamiento farmacológico , Minociclina/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bacteriemia/etiología , Método Doble Ciego , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Minociclina/administración & dosificación , Estudios Prospectivos , Tigeciclina , Adulto JovenRESUMEN
Tigecycline is a new-generation of tetracycline (glycylcyclines) and is active in vitro against bacteria that possess any of the classical genes that confer tetracycline resistance through ribosomal protection or efflux pumps. Herein, tigecycline disposition in patients with community- or hospital-acquired pneumonia was described using a population pharmacokinetic model. Additionally, the influence of covariates, such as body surface area, severity of illness, and clinical laboratory measures, on tigecycline disposition was evaluated. An intravenous loading dose of 100 mg was followed by 50 mg of tigecycline every 12 h. The final population pharmacokinetic model was a two-compartment model with linear elimination and with a relationship between tigecycline clearance and body surface area and creatinine clearance. The model was parameterized using total clearance (CL), the volume of the central compartment, distributional clearance from the central to the peripheral compartment, and volumes of distribution at steady state. Relationships between body surface area and creatinine clearance were identified as significant predictors of interindividual variability on CL. This model will serve as the basis for estimating tigecycline exposure for pharmacokinetic-pharmacodynamic analyses for efficacy and safety among patients with community- or hospital-acquired pneumonia.
Asunto(s)
Antibacterianos/farmacocinética , Infección Hospitalaria/tratamiento farmacológico , Minociclina/análogos & derivados , Neumonía/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Infección Hospitalaria/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Minociclina/farmacocinética , Minociclina/uso terapéutico , Neumonía/sangre , Tigeciclina , Adulto JovenRESUMEN
BACKGROUND: Tigecycline, a first-in-class broad-spectrum glycylcycline antibiotic, has broad-spectrum in vitro activity against bacteria commonly encountered in complicated intra-abdominal infections (cIAIs), including aerobic and facultative Gram-positive and Gram-negative bacteria and anaerobic bacteria. In the current trial, tigecycline was evaluated for safety and efficacy vs. imipenem/cilastatin in hospitalized Chinese patients with cIAIs. METHODS: In this phase 3, multicenter, open-label study, patients were randomly assigned to receive IV tigecycline or imipenem/cilastatin for =2 weeks. The primary efficacy endpoints were clinical response at the test-of-cure visit (12-37 days after therapy) for the microbiologic modified intent-to-treat and microbiologically evaluable populations. Because the study was not powered to demonstrate non-inferiority between tigecycline and imipenem/cilastatin, no formal statistical analysis was performed. Two-sided 95% confidence intervals (CIs) were calculated for the response rates in each treatment group and for differences between treatment groups for descriptive purposes. RESULTS: One hundred ninety-nine patients received >/=1 dose of study drug and comprised the modified intent-to-treat population. In the microbiologically evaluable population, 86.5% (45 of 52) of tigecycline- and 97.9% (47 of 48) of imipenem/cilastatin-treated patients were cured at the test-of-cure assessment (12-37 days after therapy); in the microbiologic modified intent-to-treat population, cure rates were 81.7% (49 of 60) and 90.9% (50 of 55), respectively. The overall incidence of treatment-emergent adverse events was 80.4% for tigecycline vs. 53.9% after imipenem/cilastatin therapy (P < 0.001), primarily due to gastrointestinal-related events, especially nausea (21.6% vs. 3.9%; P < 0.001) and vomiting (12.4% vs. 2.0%; P = 0.005). CONCLUSIONS: Clinical cure rates for tigecycline were consistent with those found in global cIAI studies. The overall safety profile was also consistent with that observed in global studies of tigecycline for treatment of cIAI, as well as that observed in analyses of Chinese patients in those studies; no novel trends were observed. TRIAL REGISTRATION: ClinicalTrials.gov NCT00136201.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Cilastatina/uso terapéutico , Imipenem/uso terapéutico , Minociclina/análogos & derivados , Peritonitis/tratamiento farmacológico , Adulto , Anciano , Antibacterianos/efectos adversos , Pueblo Asiatico , Cilastatina/efectos adversos , Combinación Cilastatina e Imipenem , Combinación de Medicamentos , Femenino , Humanos , Imipenem/efectos adversos , Masculino , Persona de Mediana Edad , Minociclina/efectos adversos , Minociclina/uso terapéutico , Tigeciclina , Resultado del TratamientoRESUMEN
OBJECTIVES: To evaluate the efficacy and safety of tigecycline in patients with selected serious infections caused by resistant Gram-negative bacteria, or failures who had received prior antimicrobial therapy or were unable to tolerate other appropriate antimicrobials. Secondary objectives included an evaluation of the microbiological efficacy of tigecycline and in vitro activity of tigecycline for resistant Gram-negative bacteria. METHODS: This open-label, Phase 3, non-comparative, multicentre study assessed the efficacy and safety of intravenous tigecycline (100 mg initially, then 50 mg 12 hourly for 7-28 days) in hospitalized patients with serious infections including complicated intra-abdominal infection; complicated skin and skin structure infection (cSSSI); community-acquired pneumonia (CAP); hospital-acquired pneumonia, including ventilator-associated pneumonia; or bacteraemia, including catheter-related bacteraemia. All patients had infections due to resistant Gram-negative organisms, including extended-spectrum beta-lactamase-producing strains, or had failed on prior therapy or could not receive (allergy or intolerance) one or more agents from three classes of commonly used antibiotics. The primary efficacy endpoint was clinical response in the microbiologically evaluable (ME) population at test of cure (TOC). Safety data included vital signs, laboratory tests and adverse events (AEs). RESULTS: In the ME population at TOC, the clinical cure rate was 72.2% [95% confidence interval (CI): 54.8-85.8], and the microbiological eradication rate was 66.7% (95% CI: 13.7-78.8). The most commonly isolated resistant Gram-negative pathogens were Acinetobacter baumannii (47%), Escherichia coli (25%), Klebsiella pneumoniae (16.7%) and Enterobacter spp. (11.0%); the most commonly diagnosed serious infection was cSSSI (67%). The most common treatment-emergent AEs were nausea (29.5%), diarrhoea (16%) and vomiting (16%), which were mild or moderate in severity. CONCLUSIONS: In this non-comparative study, tigecycline appeared safe and efficacious in patients with difficult-to-treat serious infections caused by resistant Gram-negative organisms.
Asunto(s)
Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana , Enterobacter/efectos de los fármacos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Minociclina/análogos & derivados , Infecciones por Acinetobacter/microbiología , Adulto , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Infecciones por Enterobacteriaceae/microbiología , Femenino , Hospitalización , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Minociclina/administración & dosificación , Minociclina/efectos adversos , Minociclina/farmacología , Minociclina/uso terapéutico , Tigeciclina , Resultado del TratamientoRESUMEN
This randomized, double-blind, multicenter study compared the efficacy and safety of piperacillin/tazobactam (P/T) and imipenem/cilastatin (IMP), both in combination with an aminoglycoside, in hospitalized patients with acute nosocomial pneumonia (NP). Patients with acute NP, defined as pneumonia with symptoms > or = 48 h after admission or < or =7 days after hospital discharge, received infusions of 4 g/500 mg P/T or 500 mg/500 mg IMP every 6 h. Endpoints were clinical cure and microbiological response rates; pathogen eradication rates; length of hospital stay; hospital readmissions; and adverse events (AEs). Of 437 patients in the intent-to-treat population, 197 were efficacy evaluable. At test-of-cure, response rates were similar between groups. Within the efficacy evaluable population, 68% of P/T patients and 61% of IMP patients were clinically cured (P = 0.256). Microbiological responses for P/T and IMP patients were: eradication, 64% versus 59%; persistence, 29% versus 21%; relapse, 0% versus 5%; and superinfection, 7% versus 15%, respectively. Gram-positive isolates were eradicated in 83% of P/T patients and 75% of IMP patients; Gram-negative pathogens were eradicated in 72% of P/T patients and 77% of IMP patients. Treatment groups had similar number of mean hospital days, readmission rates, and frequency of AEs. This study showed that P/T administered four times per day was as safe and efficacious as IMP in treating hospitalized patients with NP.
Asunto(s)
Antibacterianos/uso terapéutico , Neumonía Asociada al Ventilador/tratamiento farmacológico , Antibacterianos/efectos adversos , Cilastatina/administración & dosificación , Infección Hospitalaria/tratamiento farmacológico , Método Doble Ciego , Quimioterapia Combinada , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Imipenem/administración & dosificación , Masculino , Persona de Mediana Edad , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/análogos & derivados , Piperacilina/administración & dosificación , Inhibidores de Proteasas/administración & dosificación , Tazobactam , Tobramicina/administración & dosificación , Resultado del TratamientoRESUMEN
A phase 3, randomized, double-blind trial was conducted in subjects with diabetic foot infections without osteomyelitis (primary study) or with osteomyelitis (substudy) to determine the efficacy and safety of parenteral (intravenous [iv]) tigecycline (150 mg once-daily) versus 1 g once-daily iv ertapenem ± vancomycin. Among 944 subjects in the primary study who received ≥1 dose of study drug, >85% had type 2 diabetes; ~90% had Perfusion, Extent, Depth/tissue loss, Infection, and Sensation infection grade 2 or 3; and ~20% reported prior antibiotic failure. For the clinically evaluable population at test-of-cure, 77.5% of tigecycline- and 82.5% of ertapenem ± vancomycin-treated subjects were cured. Corresponding rates for the clinical modified intent-to-treat population were 71.4% and 77.9%, respectively. Clinical cure rates in the substudy were low (<36%) for a subset of tigecycline-treated subjects with osteomyelitis. Nausea and vomiting occurred significantly more often after tigecycline treatment (P = 0.003 and P < 0.001, respectively), resulting in significantly higher discontinuation rates in the primary study (nausea P = 0.007, vomiting P < 0.001). In the primary study, tigecycline did not meet criteria for noninferiority compared with ertapenem ± vancomycin in the treatment of subjects with diabetic foot infections.
Asunto(s)
Antibacterianos/uso terapéutico , Pie Diabético/complicaciones , Pie Diabético/tratamiento farmacológico , Minociclina/análogos & derivados , Osteomielitis/tratamiento farmacológico , beta-Lactamas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Ertapenem , Femenino , Humanos , Masculino , Persona de Mediana Edad , Minociclina/efectos adversos , Minociclina/uso terapéutico , Náusea/inducido químicamente , Náusea/epidemiología , Tigeciclina , Resultado del Tratamiento , Vancomicina/efectos adversos , Vancomicina/uso terapéutico , Vómitos/inducido químicamente , Vómitos/epidemiología , Adulto Joven , beta-Lactamas/efectos adversosRESUMEN
BACKGROUND: To compare the monotherapy of tigecycline with vancomycin-aztreonam in hospitalized patients from India and Taiwan with complicated skin and skin structure infections (cSSSIs). METHODS: Safety and efficacy data were analyzed for Indian (n = 86) and Taiwanese (n = 41) patients hospitalized with cSSSIs who participated in two international Phase 3, randomized, double-blind studies. RESULTS: Patients were treated for 5-14 days. Cure rates at the test-of-cure assessment (12-92 days post-therapy) were generally similar between tigecycline and vancomycin-aztreonam in the clinically evaluable populations (India, 83.3% vs. 75.8%; Taiwan, 78.6% vs. 90%) and in the clinical modified intent-to-treat populations (India, 78.6% vs. 66.7%; Taiwan, 73.3% vs. 75.0%). Nausea and vomiting occurred more frequently with tigecycline, but overall safety and tolerability were comparable between the two treatments. CONCLUSIONS: Tigecycline monotherapy is a safe and effective therapy for cSSSIs in geographically distinct populations in Asia.
Asunto(s)
Antibacterianos/uso terapéutico , Aztreonam/uso terapéutico , Minociclina/análogos & derivados , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Vancomicina/uso terapéutico , Adulto , Anciano , Antibacterianos/efectos adversos , Aztreonam/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , India , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Minociclina/efectos adversos , Minociclina/uso terapéutico , Náusea/etiología , Taiwán , Tigeciclina , Vancomicina/efectos adversos , Vómitos/etiologíaRESUMEN
Tigecycline exhibits potent in vitro activity against many community-acquired pneumonia (CAP) pathogens, including antibiotic-resistant ones. Its spectrum of activity and ability to penetrate lung tissue suggest it may be effective for hospitalized CAP patients. Hospitalized CAP patients (n=418) were randomized to receive intravenous (i.v.) tigecycline or levofloxacin. Patients could be switched to oral levofloxacin after receiving 6 or more doses of i.v. study medication. Therapy duration was 7 to 14 days. Coprimary efficacy end points were clinical responses in the clinically evaluable (CE: tigecycline, n=138; levofloxacin, n=156) and clinical modified intent-to-treat (c-mITT: tigecycline, n=191; levofloxacin, n=203) populations at test-of-cure (TOC). Safety was assessed in the mITT population (tigecycline, n=208; levofloxacin, n=210). Cure rates in tigecycline and levofloxacin groups were comparable in CE (90.6% versus 87.2%, respectively) and c-mITT (78% versus 77.8%, respectively) populations at TOC. Nausea and vomiting occurred in significantly more tigecycline-treated patients; elevated alanine aminotransferase and aspartate aminotransferase levels were reported in significantly more levofloxacin-treated patients. There were no significant differences in hospital length of stay, median duration of i.v. or oral antibiotic treatments, hospital readmissions, or number of patients switched to oral levofloxacin. Tigecycline was safe, effective, and noninferior to levofloxacin in hospitalized patients with CAP.