RESUMO
BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).
Assuntos
Antibacterianos , Ácidos Borínicos , Ácidos Carboxílicos , Cefepima , Meropeném , Infecções Urinárias , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Administração Intravenosa , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , beta-Lactamases/administração & dosagem , beta-Lactamases/efeitos adversos , beta-Lactamases/uso terapêutico , Ácidos Borínicos/administração & dosagem , Ácidos Borínicos/efeitos adversos , Ácidos Borínicos/uso terapêutico , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/uso terapêutico , Cefepima/administração & dosagem , Cefepima/efeitos adversos , Cefepima/uso terapêutico , Quimioterapia Combinada , Hospitalização , Meropeném/administração & dosagem , Meropeném/efeitos adversos , Meropeném/uso terapêutico , Testes de Sensibilidade Microbiana , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Farmacorresistência BacterianaRESUMO
CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.
Assuntos
Antibacterianos , Cefepima , Cefalosporinas , Meropeném , Testes de Sensibilidade Microbiana , Infecções Urinárias , beta-Lactamases , Humanos , Meropeném/uso terapêutico , Meropeném/farmacologia , Cefepima/uso terapêutico , Cefepima/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , beta-Lactamases/genética , Adulto , Feminino , Masculino , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pessoa de Meia-Idade , Método Duplo-Cego , Proteínas de Bactérias/genética , Genótipo , Fenótipo , Idoso , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Resultado do Tratamento , Ácidos Borínicos , Ácidos CarboxílicosRESUMO
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug being developed for the treatment of serious bacterial infections. This open-label, 3-period, fixed sequence study evaluated the effect of gastric acid-reducing agents, aluminum hydroxide/magnesium hydroxide/simethicone, and omeprazole on the pharmacokinetics (PK) of tebipenem (TBP), the active moiety, following coadministration with immediate release TBP-PI-HBr during fasting. In Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 × 300 mg tablets). In Period 2, subjects received a single oral dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension co-administered with a single dose of TBP-PI-HBr 600 mg. In Period 3, subjects received a single oral dose of omeprazole 40 mg once daily over 5 days, followed by single dose administration of TBP-PI-HBr 600 mg on day 5. In each period, whole blood samples were obtained prior to, and up to 24 h, following TBP-PI-HBr dose administration in order to characterize TBP PK. A 7-day washout was required between periods. Twenty subjects were enrolled and completed the study. Following co-administration of TBP-PI-HBr with either aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole, total TBP exposure (area under the curve [AUC]) was approximately 11% (geometric mean ratio 89.2, 90% confidence interval: 83,2, 95.7) lower, and Cmax was 22% (geometric mean ratio 78.4, 90% confidence interval: 67.9, 90.6) and 43% (geometric mean ratio 56.9, 90% confidence interval: 49.2, 65.8) lower, respectively, compared to administration of TBP-PI-HBr alone. Mean TBP elimination half-life (t1/2) was generally comparable across treatments (range: 1.0 to 1.5 h). Concomitant administration of TBP-PI-HBr with omeprazole or aluminum hydroxide/magnesium hydroxide/simethicone is not expected to impact the efficacy of TBP-PI-HBr, as there is minimal impact on TBP plasma AUC, which is the pharmacodynamic driver of efficacy. Co-administration was generally safe and well tolerated.
Assuntos
Antiácidos , Antiulcerosos , Adulto , Humanos , Administração Oral , Hidróxido de Alumínio/farmacologia , Antiácidos/farmacologia , Estudos Cross-Over , Interações Medicamentosas , Hidróxido de Magnésio/farmacologia , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , SimeticoneRESUMO
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug of pharmacologically active moiety tebipenem (TBP), which is a carbapenem with activity against multidrug-resistant Gram-negative pathogens. Conversion from the prodrug to the active moiety, namely, TBP, occurs in the enterocytes of the gastrointestinal tract via intestinal esterases. The absorption, metabolism, and excretion in humans were evaluated, following the administration of a single oral dose of [14C]-TBP-PI-HBr. Healthy male subjects (n = 8) received a single 600 mg oral dose of TBP-PI-HBr containing approximately 150 µCi of [14C]-TBP-PI-HBr. Blood, urine, and fecal samples were collected to determine the total radioactivity, concentrations of TBP (plasma only), and metabolite profiling and identification. The overall mean recovery of the total radioactivity in urine (38.7%) and feces (44.6%) combined was approximately 83.3% of the administered dose, with individual recoveries ranging from 80.1% to 85.0%. Plasma TBP LC-MS/MS and metabolite profiling data suggest that TBP was the main circulating component in plasma and that it accounts for approximately 54% of the total plasma radioactivity, based on the plasma AUC ratio of TBP/total radioactivity. The ring-open metabolite LJC 11562 was another major component in plasma (>10%). TBP (M12), LJC 11562, and four trace to minor metabolites were identified/characterized in the urine. TBP-PI, TBP (M12), and 11 trace to minor metabolites were identified/characterized in the feces. The renal and fecal routes are major clearance pathways in the elimination of [14C]-TBP-PI-HBr, with a mean combined recovery of 83.3%. TBP and its inactive ring-open metabolite LJC 11562 were the major circulating metabolites in the plasma.
Assuntos
Pró-Fármacos , Humanos , Masculino , Cromatografia Líquida , Espectrometria de Massas em Tandem , Fezes , Administração Oral , Radioisótopos de CarbonoRESUMO
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales. This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg). Subjects in cohort 5 received single-dose administration (600 mg) in 2 separate periods: pre-HD (period 2) and post-HD (period 1). Pharmacokinetic (PK) parameters for TBP, the active moiety, were determined using noncompartmental analysis. Compared with cohort 1, the TBP plasma area under the curve (AUC) increased 1.4- to 4.5-fold among cohorts 2 to 4, the maximum concentration of drug in plasma (Cmax) increased up to 1.3-fold and renal clearance (CLR) decreased from 13.4 L/h to 2.4 L/h as the severity of RI increased. Plasma TBP concentrations decreased over 8 to 12 h in cohorts 1 to 4, and apparent total body clearance (CL/F) correlated (R2 = 0.585) with creatinine clearance (CLCR). TBP urinary excretion ranged from 38% to 64% of the administered dose for cohorts 1 to 4. Subjects in cohort 5 had an approximately 7-fold increase in TBP AUC and elimination half-life (t1/2) versus cohort 1. After 4 h of HD, mean TBP plasma exposure decreased by approximately 40%. Overall, TBP plasma exposure increased with increasing RI, highlighting the renal route importance in TBP elimination. A dose reduction of TBP-PI-HBr may be needed in patients with RI (CLCR of ≤50 mL/min) and those with ESRD on HD. TBP-PI-HBr was well tolerated across all cohorts. (This study has been registered at ClinicalTrials.gov under registration no. NCT04178577.).
Assuntos
Falência Renal Crônica , Insuficiência Renal , Área Sob a Curva , Carbapenêmicos/uso terapêutico , Humanos , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/tratamento farmacológico , Monobactamas/uso terapêutico , Insuficiência Renal/tratamento farmacológicoRESUMO
BACKGROUND: Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. METHODS: In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). RESULTS: There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. CONCLUSIONS: Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. CLINICAL TRIALS REGISTRATION: NCT02559310.
Assuntos
Diterpenos/uso terapêutico , Moxifloxacina/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Compostos Policíclicos/uso terapêutico , Tioglicolatos/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Diterpenos/administração & dosagem , Diterpenos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Moxifloxacina/administração & dosagem , Moxifloxacina/efeitos adversos , Pneumonia Bacteriana/metabolismo , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tioglicolatos/administração & dosagem , Tioglicolatos/efeitos adversos , PleuromutilinasRESUMO
IMPORTANCE: New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care. OBJECTIVE: To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP. DESIGN, SETTING, AND PARTICIPANTS: A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018. INTERVENTIONS: Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368). MAIN OUTCOMES AND MEASURES: The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response. RESULTS: Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, -4.4% to ∞]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, -1.6% [1-sided 97.5% CI, -6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ∞]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group). CONCLUSIONS AND RELEVANCE: Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92.
RESUMO
Objectives: This analysis evaluated the clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates pooled from the adult Phase III clinical trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) or nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). Methods: Baseline isolates from five Phase III randomized controlled trials of ceftazidime/avibactam versus predominantly carbapenem comparators in patients with cIAI (RECLAIM 1 and 2; NCT01499290 and RECLAIM 3; NCT01726023), cUTI (RECAPTURE 1 and 2; NCT01595438 and NCT01599806), NP including VAP (REPROVE; NCT01808092) and cIAI or cUTI caused by ceftazidime-non-susceptible Gram-negative pathogens (REPRISE; NCT01644643) were tested for MDR status and susceptibility to ceftazidime/avibactam and carbapenem-based comparators using CLSI broth microdilution methodology. Microbiological and clinical responses for patients with ≥1 MDR Enterobacteriaceae or P. aeruginosa isolate were assessed at the test-of-cure (TOC) visit. Results: In the pooled microbiologically modified ITT population, 1051 patients with MDR Enterobacteriaceae and 95 patients with MDR P. aeruginosa isolates were identified. Favourable microbiological response rates at TOC for all MDR Enterobacteriaceae and MDR P. aeruginosa were 78.4% and 57.1%, respectively, for ceftazidime/avibactam and 71.6% and 53.8%, respectively, for comparators. The proportions of patients with ≥1 MDR isolate who were clinically cured at TOC were similar in the ceftazidime/avibactam (85.4%) and comparator (87.9%) arms. Conclusions: Ceftazidime/avibactam demonstrated similar clinical efficacy to predominantly carbapenem comparators against MDR Enterobacteriaceae and P. aeruginosa, and may be a suitable alternative to carbapenem-based therapies for cIAI, cUTI and NP/VAP caused by MDR Gram-negative pathogens.
Assuntos
Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções Intra-Abdominais/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Adulto , Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Humanos , Infecções Intra-Abdominais/microbiologia , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Resultado do Tratamento , Inibidores de beta-Lactamases/farmacologiaRESUMO
BACKGROUND: When combined with ceftazidime, the novel non-ß-lactam ß-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). METHODS: The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%. RESULTS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. CLINICAL TRIALS REGISTRATION: NCT01499290 and NCT01500239.
Assuntos
Antibacterianos , Compostos Azabicíclicos , Ceftazidima , Infecções Intra-Abdominais/tratamento farmacológico , Metronidazol , Tienamicinas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/efeitos adversos , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/administração & dosagem , Ceftazidima/efeitos adversos , Ceftazidima/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Infecções Intra-Abdominais/epidemiologia , Masculino , Meropeném , Metronidazol/administração & dosagem , Metronidazol/efeitos adversos , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Tienamicinas/administração & dosagem , Tienamicinas/efeitos adversos , Tienamicinas/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the efficacy and safety of ceftazidime-avibactam and doripenem in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/acute pyelonephritis were randomized 1:1 to ceftazidime-avibactam 2000 mg/500 mg every 8 hours or doripenem 500 mg every 8 hours (doses adjusted for renal function), with possible oral antibiotic switch after ≥5 days (total treatment duration up to 10 days or 14 days for patients with bacteremia). RESULTS: Of 1033 randomized patients, 393 and 417 treated with ceftazidime-avibactam and doripenem, respectively, were eligible for the primary efficacy analyses; 19.6% had ceftazidime-nonsusceptible baseline pathogens. Noninferiority of ceftazidime-avibactam vs doripenem was demonstrated for the US Food and Drug Administration co-primary endpoints of (1) patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients (difference, 4.0% [95% confidence interval {CI}, -2.39% to 10.42%]); and (2) combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients (difference, 6.7% [95% CI, .30% to 13.12%]). Microbiological eradication at TOC (European Medicines Agency primary endpoint) occurred in 304 of 393 (77.4%) ceftazidime-avibactam vs 296 of 417 (71.0%) doripenem patients (difference, 6.4% [95% CI, .33% to 12.36%]), demonstrating superiority at the 5% significance level. Both treatments showed similar efficacy against ceftazidime-nonsusceptible pathogens. Ceftazidime-avibactam had a safety profile consistent with that of ceftazidime alone. CONCLUSIONS: Ceftazidime-avibactam was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting. CLINICAL TRIALS REGISTRATION: NCT01595438; NCT01599806.
Assuntos
Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Carbapenêmicos/uso terapêutico , Ceftazidima/uso terapêutico , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/efeitos adversos , Carbapenêmicos/administração & dosagem , Carbapenêmicos/efeitos adversos , Ceftazidima/administração & dosagem , Ceftazidima/efeitos adversos , Doripenem , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pielonefrite/complicações , Infecções Urinárias/complicaçõesRESUMO
The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized ß-lactam resistance mechanisms from complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials. Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MICs of ≥ 2 µg/ml (69 isolates) and nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥ 16 µg/ml were characterized for their narrow- and extended-spectrum ß-lactamase (ESBL) content. Enterobacteriaceae (one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥ 2 and ≥ 16 µg/ml, respectively, were tested for carbapenemases. All cUTI E. coli had the lineage background investigated (ST131-like versus non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test of cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen positive). All screen-positive cUTI pathogens were CTX-M-producing E. coli, except for one E. cloacae isolate with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other ß-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBL Enterobacteriaceae isolate was recovered at the baseline visit. When an ESBL Enterobacteriaceae isolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-like E. coli isolate was recovered at baseline, as when a non-ST131-like isolate was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.
Assuntos
Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/genética , beta-Lactamases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase II como Assunto , Combinação de Medicamentos , Feminino , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Antimicrobials cause perturbations in the composition and diversity of the host microbiome. We aimed to compare gut microbiome perturbations caused by oral tebipenem pivoxil hydrobromide (a novel carbapenem) and by amoxicillin-clavulanic acid (an orally administered ß-lactam-ß-lactam inhibitor combination widely used in clinical practice). METHODS: We did a phase 1, single-centre, randomised, parallel-group, active-control trial to evaluate the effect of tebipenem pivoxil hydrobromide on the human gut microbiota. Healthy participants aged 18 years or older with no documented illnesses during recruitment were enrolled at Karolinska University Hospital (Stockholm, Sweden). Study participants were stratified by sex and block-randomised in a 1:1 ratio to treatment with either tebipenem pivoxil hydrobromide (600 mg orally every 8 h) or amoxicillin-clavulanic acid (500 mg amoxicillin and 125 mg clavulanic acid orally every 8 h). The study included 10 days of treatment (days 1-10) and four follow-up visits (days 14, 21, 90, and 180). The trial was open-label for clinical investigators and patients, but masked for microbiology investigators. Faecal samples were collected at all visits. Sequencing of 16S rDNA was used to measure the diversity metrics, and quantitative culture to quantify selected taxa. The primary outcomes were changes in the α and ß diversity and log count of colony-forming units for selected taxa between samples compared with baseline (day 1), and whether any changes reverted during the follow-up period. The analyses were done in the intention-to-treat population. This study was registered with ClinicalTrials.gov (NCT04376554). FINDINGS: The study was conducted between Jan 23, 2020, and April 6, 2021. 49 volunteers were screened for eligibility, among whom 30 evaluable participants (14 men and 16 women) were assigned: 15 (50%) to the tebipenem pivoxil hydrobromide group and 15 (50%) to the amoxicillin-clavulanic acid group. Baseline characteristics were similar between groups. Complete follow-up was available for all participants, and all participants except one completed treatment as assigned. The diversity metrics showed significant changes from baseline during the treatment period. Significant decreases in richness were observed on days 4-10 (p≤0·0011) in the amoxicillin-clavulanic acid group and on days 4-14 (p≤0·0019) in the tebipenem pivoxil hydrobromide group. Similarly, evenness was significantly decreased during treatment in the amoxicillin-clavulanic acid group (day 4, p=0·030) and the tebipenem pivoxil hydrobromide group (days 4-10, p<0·0001) compared with baseline. Quantitative cultures showed significant decreases in Enterobacterales (days 4-7, p≤0·0030), Enterococcus spp (days 4-14, p=0·025 to p<0·0001), Bifidobacterium spp (days 2-4, p≤0·026), and Bacteroides spp (days 4-10, p≤0·030) in the tebipenem pivoxil hydrobromide group. Similarly, in amoxicillin-clavulanic acid recipients, significant changes were observed in Enterobacterales (days 4-10, p≤0·048), Bifidobacterium spp (days 2-4, p≤0·013), and Lactobacillus spp (days 2-4, p≤0·020). Samples from the follow-up period were not significantly different from those at baseline in ß diversity analysis (PERMANOVA, p>0·99). By the end of the study, no significant change was observed compared with baseline in either group. There were no deaths or severe adverse events. INTERPRETATION: The impact of tebipenem pivoxil hydrobromide on the gut microbiome was similar to that of amoxicillin-clavulanic acid. The safety of antibiotic use with regard to the microbiome should be given attention, as dysbiosis is associated with health and disease. FUNDING: Spero Therapeutics.
Assuntos
Carbapenêmicos , Microbioma Gastrointestinal , Masculino , Adulto , Humanos , Feminino , Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Suécia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , MonobactamasAssuntos
Ceftazidima , Doripenem , Compostos Azabicíclicos , Combinação de Medicamentos , Humanos , Pielonefrite , Infecções UrináriasRESUMO
To determine genetic factors predisposing to neurological complications following West Nile virus infection, we analyzed a cohort of 560 neuroinvasive case patients and 950 control patients for 13 371 mostly nonsynonymous single-nucleotide polymorphisms (SNPs). The top 3 SNPs on the basis of statistical significance were also in genes of biological plausibility: rs2066786 in RFC1 (replication factor C1) (P = 1.88 × 10(-5); odds ratio [OR], 0.68 [95% confidence interval {CI}, .56-.81]); rs2298771 in SCN1A (sodium channel, neuronal type I α subunit) (P = 5.87 × 10(-5); OR, 1.47 [95% CI, 1.21-1.77]); and rs25651 in ANPEP (ananyl aminopeptidase) (P = 1.44 × 10(-4); OR, 0.69 [95% CI, .56-.83]). Additional genotyping of these SNPs in a separate sample of 264 case patients and 296 control patients resulted in a lack of significance in the replication cohort; joint significance was as follows: rs2066786, P = .0022; rs2298771, P = .005; rs25651, P = .042. Using mostly nonsynonymous variants, we therefore did not identify genetic variants associated with neuroinvasive disease.
Assuntos
Encefalite Viral/genética , Predisposição Genética para Doença , Meningite Viral/genética , Paralisia/genética , Polimorfismo de Nucleotídeo Único , Febre do Nilo Ocidental/genética , 2',5'-Oligoadenilato Sintetase/genética , Adulto , Idoso , Alelos , Antígenos CD13/genética , Estudos de Casos e Controles , Encefalite Viral/virologia , Éxons , Feminino , Genótipo , Humanos , Masculino , Meningite Viral/virologia , Pessoa de Meia-Idade , Família Multigênica , Canal de Sódio Disparado por Voltagem NAV1.1 , Proteínas do Tecido Nervoso/genética , Paralisia/virologia , Regiões Promotoras Genéticas , Receptores CCR5/genética , Proteína de Replicação C/genética , Canais de Sódio/genética , Febre do Nilo Ocidental/complicaçõesRESUMO
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug of tebipenem (TBP), the active moiety, currently in development for treating serious bacterial infections. This study assessed the bioequivalence (BE) of the clinical trial and registration tablet formulations of TBP-PI-HBr and evaluated the effect of food on the pharmacokinetics (PKs) of tebipenem. This was a single center, open-label, randomized, single-dose, three-sequence, four-period crossover, BE, and food-effect study. Subjects received single 600 mg oral doses of TBP-PI-HBr as the reference clinical trial tablet (treatment A) and test registration tablet (treatment B) formulations in alternating sequence while fasting, and then the test formulation under fed conditions. Whole blood samples were collected predose and at specified intervals up to 24 h postdose to evaluate TBP PK parameters. Safety and tolerability were monitored. Thirty-six healthy, adult subjects were enrolled and completed the study. The criteria for BE were met for the TBP-PI-HBr test (registration tablet) and reference (clinical trial tablet) formulations as the 90% confidence intervals for the geometric mean ratios for TBP area under the curve (AUC)0-t , AUC0-inf , and maximum plasma concentration (Cmax ) fell within the established 80% to 125% BE limits. Dosing with food had no meaningful effect on TBP PK parameters. Five (14%) subjects reported adverse events (AEs) of mild severity. No deaths, serious AEs, or discontinuations due to AEs were reported, and no clinically relevant electrocardiograms, vital signs, or safety laboratory findings were observed. The study results demonstrate the BE of oral TBP-PI-HBr registration and clinical trial tablet formulations and indicate that TBP-PI-HBr can be administered without regard to meals.
Assuntos
Equivalência Terapêutica , Administração Oral , Adulto , Carbapenêmicos , Voluntários Saudáveis , Humanos , ComprimidosRESUMO
BACKGROUND: Concern has been raised over the practice of unnecessary double anaerobic coverage therapy (DACT) in the hospital setting. However, the incidence of and risk factors for unnecessary DACT are not well studied. On 8 September 2008, the antimicrobial stewardship programme (ASP) at our institution was modified such that several antibiotics, including ampicillin/sulbactam and metronidazole, no longer required pre-approval. We anticipated that this change would increase both unnecessary DACT and target antibiotic consumption. METHODS: A nested case-control study was conducted to determine the cumulative incidence of and risk factors for unnecessary DACT. Cases were subjects who received unnecessary DACT while controls were subjects who did not receive DACT or who received necessary DACT. Segmented regression analysis was subsequently performed to evaluate the impact of ASP changes on unnecessary DACT and consumption of target antibiotics. RESULTS: From October 2007 to September 2009, the cumulative incidence of unnecessary DACT was 2.3% [95% confidence interval (CI) 1.7-3.1]. Independent risk factors for unnecessary DACT [adjusted odds ratio (95% CI); P value] included hospitalization on a surgical ward [3.51 (1.03-12.02); Pâ=â0.002], hospitalization on an obstetrics and gynaecology ward [9.07 (2.54-32.40); Pâ=â0.002] and underlying metastatic malignancy [3.18 (1.38-7.09); Pâ=â0.006]. The ASP change was associated with an increase in ampicillin/sulbactam and metronidazole consumption. However, there was no significant impact on unnecessary DACT prescribing. CONCLUSIONS: Although uncommon, unnecessary DACT is more prevalent in specific services. Future qualitative studies focusing on these specific subgroups would be useful in elucidating this problem more clearly. The ASP changes were not associated with increases in unnecessary DACT.
Assuntos
Antibacterianos/administração & dosagem , Bactérias Anaeróbias , Infecções Bacterianas/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Uso de Medicamentos/estatística & dados numéricos , Prescrição Inadequada/estatística & dados numéricos , Ampicilina/administração & dosagem , Antibacterianos/uso terapêutico , Infecções Bacterianas/microbiologia , Estudos de Casos e Controles , Esquema de Medicação , Hospitais , Humanos , Metronidazol/administração & dosagem , Padrões de Prática Médica , Sulbactam/administração & dosagemRESUMO
PURPOSE OF REVIEW: Emergence of drug-resistant bacteria and new or changing infectious pathogens is an important public health problem. Transmission of these pathogens in an acute care setting may occur frequently if proper precautions are not taken. Despite several guidelines and an abundance of literature on the prevention of transmission of epidemiologically important organisms in the healthcare setting, substantial controversy exists. This review focuses on recent data regarding the use of infection control and isolation precautions. RECENT FINDINGS: New data are available, but the conflict surrounding the use of active surveillance of methicillin-resistant Staphylococcus aureus (MRSA) has not been resolved. The emergence of multidrug-resistant Gram-negative bacteria has prompted a greater interest in infection control strategies for prevention of their spread. Outbreaks of Clostridium difficile have responded to broad infection control initiatives, but further research is required to determine whether the best infection control precautions are being utilized. SUMMARY: Effective prevention of the transmission of pathogens within the healthcare system requires a multifaceted approach. Existing guidelines should be used to create institutional policies specific to individual patient populations, problem pathogens and the ability to practically implement various infection control procedures. Despite ongoing study, the use of active surveillance to prevent transmission of MRSA continues to be a complex, controversial and challenging issue.
Assuntos
Infecções Bacterianas/prevenção & controle , Infecção Hospitalar/prevenção & controle , Farmacorresistência Bacteriana Múltipla , Instalações de Saúde , Controle de Infecções/métodos , Infecções Bacterianas/microbiologia , Infecções Bacterianas/transmissão , Infecção Hospitalar/microbiologia , Infecção Hospitalar/transmissão , Humanos , Isolamento de PacientesRESUMO
Optimal measures for the prevention of cytomegalovirus (CMV) in high-risk orthotopic liver transplant (OLT) patients are unknown. The charts of high-risk OLT recipients with 12 months of follow-up who were transplanted over a 44-month period were reviewed. The incidence of CMV disease in CMV-seropositive donor/CMV-seronegative recipient patients receiving valganciclovir or ganciclovir prophylaxis was compared. Sixty-six patients met the inclusion criteria and were treated with 1 of 3 prophylactic regimens: valganciclovir (900 mg daily; 27 patients), oral ganciclovir (1000 mg every 8 hours; 17 patients), or intravenous ganciclovir (6 mg/kg daily; 22 patients). Eight CMV cases occurred, all after completion of the prophylaxis. The combined incidence of CMV disease with intravenous and oral ganciclovir was lower than the incidence in valganciclovir recipients (P = 0.056; relative risk, 4.33; 95% confidence interval, 0.94-19.87). CMV disease occurred in 22.2% of valganciclovir recipients, 4.5% of intravenous ganciclovir recipients, and 5.9% of oral ganciclovir recipients. In conclusion, late-onset CMV disease occurred more frequently among high-risk liver transplant recipients treated with valganciclovir prophylaxis. The 4-fold higher incidence of CMV disease in our study supports the avoidance of valganciclovir for prophylaxis in high-risk OLT patients. Liver Transpl 15:963-967, 2009. (c) 2009 AASLD.
Assuntos
Infecções por Citomegalovirus/epidemiologia , Citomegalovirus/metabolismo , Ganciclovir/análogos & derivados , Ganciclovir/uso terapêutico , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Administração Oral , Adulto , Antivirais/uso terapêutico , Biópsia , Infecções por Citomegalovirus/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Fatores de Tempo , ValganciclovirRESUMO
Eighteen patients received tigecycline as treatment for infection due to multidrug-resistant gram-negative bacilli, including Acinetobacter baumannii and Klebsiella pneumoniae carbapenemase- and extended-spectrum beta-lactamase-producing Enterobacteriaceae. Pretherapy minimum inhibitory concentration values for tigecycline predicted clinical success. Observed evolution of resistance during therapy raises concern about routine use of tigecycline in treatment of such infections when other therapies are available.