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1.
Clin Infect Dis ; 69(11): 1912-1918, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30722013

RESUMO

BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.


Assuntos
Antibacterianos/uso terapêutico , Pneumonia Bacteriana/microbiologia , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Consenso , Cuidados Críticos/métodos , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Humanos , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Resultado do Tratamento
2.
Artigo em Inglês | MEDLINE | ID: mdl-30988146

RESUMO

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infection (ABSSSI) caused by Gram-positive bacteria in the United States, Europe, and other countries. In this multicenter, double-blind, phase 3 study, 598 adult ABSSSI patients in China, Taiwan, the Philippines, and the United States were randomized to receive 200 mg of tedizolid, intravenously (i.v.)/orally (p.o.), once daily for 6 days or 600 mg of linezolid, i.v./p.o. twice daily for 10 days. The primary endpoint was early clinical response rate at 48 to 72 h. Secondary endpoints included programmatic and investigator-assessed outcomes at end-of-therapy (EOT) and posttherapy evaluation (PTE) visits. Safety was also evaluated. In the intent-to-treat (ITT) population, 75.3% of tedizolid-treated patients and 79.9% of linezolid-treated patients were early responders (treatment difference, -4.6%; 95% confidence interval [CI], -11.2, 2.2). After exclusion of patients who never received the study drug (tedizolid, n = 8; linezolid, n = 1; modified ITT), comparable early response rates were observed (tedizolid, 77.4%; linezolid, 80.1%; treatment difference, -2.7%; 95% CI, -9.4, 3.9). Secondary endpoints showed high and similar clinical success rates in the ITT and clinically evaluable (CE) populations at EOT and PTE visits (e.g., CE-PTE for tedizolid, 90.4%; for linezolid, 93.5%). Both drugs were well tolerated, and no death occurred. Eight patients experienced phlebitis with tedizolid while none did with linezolid; hence, drug-related treatment-emergent adverse events were reported in a slightly higher proportion in the tedizolid (20.9%) arm than in the linezolid arm (15.8%). The study demonstrated that tedizolid in a primarily Asian population was an efficacious and well-tolerated treatment option for ABSSSI patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02066402.).


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Organofosfatos/efeitos adversos , Organofosfatos/uso terapêutico , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Dermatopatias Bacterianas/tratamento farmacológico , Pele/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Eur Respir J ; 41(5): 1107-15, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23018904

RESUMO

This phase II, randomised, double-blind, multicentre study (NCT00930982) investigated the safety and efficacy of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis. Adults who were culture positive for pre-defined potential respiratory pathogens (including Pseudomonas aeruginosa and Haemophilus influenzae) were randomised to ciprofloxacin DPI 32.5 mg or placebo administered twice daily for 28 days (with 56 days of follow-up). Bacterial density in sputum (primary end-point), pulmonary function tests, health-related quality of life and safety were monitored throughout the study. 60 subjects received ciprofloxacin DPI 32.5 mg and 64 received placebo. Subjects on ciprofloxacin DPI had a significant reduction (p<0.001) in total sputum bacterial load at the end of treatment (-3.62 log10 CFU·g(-1) (range -9.78-5.02 log10 CFU·g(-1))) compared with placebo (-0.27 log10 CFU·g(-1) (range -7.96-5.25 log10 CFU·g(-1))); the counts increased thereafter. In the ciprofloxacin DPI group, 14 (35%) out of 40 subjects reported pathogen eradication at end of treatment versus four (8%) out of 49 in the placebo group (p=0.001). No abnormal safety results were reported and rates of bronchospasm were low. Ciprofloxacin DPI 32.5 mg twice daily for 28 days was well tolerated and achieved significant reductions in total bacterial load compared with placebo in subjects with non-cystic fibrosis bronchiectasis.


Assuntos
Bronquiectasia/tratamento farmacológico , Ciprofloxacina/administração & dosagem , Inaladores de Pó Seco , Administração por Inalação , Idoso , Antibacterianos/administração & dosagem , Carga Bacteriana , Contagem de Colônia Microbiana , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Inflamação , Pneumopatias/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pós , Pseudomonas aeruginosa , Resultado do Tratamento
4.
Eur Respir J ; 40(1): 17-27, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22135277

RESUMO

Bacterial infections causing acute exacerbations of chronic obstructive pulmonary disease (AECOPD) frequently require antibacterial treatment. More evidence is needed to guide antibiotic choice. The Moxifloxacin in Acute Exacerbations of Chronic Bronchitis TriaL (MAESTRAL) was a multiregional, randomised, double-blind non-inferiority outpatient study. Patients were aged ≥ 60 yrs, with an Anthonisen type I exacerbation, a forced expiratory volume in 1 s < 60% predicted and two or more exacerbations in the last year. Following stratification by steroid use patients received moxifloxacin 400 mg p.o. q.d. (5 days) or amoxicillin/clavulanic acid 875/125 mg p.o. b.i.d. (7 days). The primary end-point was clinical failure 8 weeks post-therapy in the per protocol population. Moxifloxacin was noninferior to amoxicillin/clavulanic acid at the primary end-point (111 (20.6%) out of 538, versus 114 (22.0%) out of 518, respectively; 95% CI -5.89-3.83%). In patients with confirmed bacterial AECOPD, moxifloxacin led to significantly lower clinical failure rates than amoxicillin/clavulanic acid (in the intent-to-treat with pathogens, 62 (19.0%) out of 327 versus 85 (25.4%) out of 335, respectively; p=0.016). Confirmed bacterial eradication at end of therapy was associated with higher clinical cure rates at 8 weeks post-therapy overall (p=0.0014) and for moxifloxacin (p=0.003). Patients treated with oral corticosteroids had more severe disease and higher failure rates. The MAESTRAL study showed that moxifloxacin was as effective as amoxicillin/clavulanic acid in the treatment of outpatients with AECOPD. Both therapies were well tolerated.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/uso terapêutico , Compostos Aza/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Antibacterianos/efeitos adversos , Compostos Aza/efeitos adversos , Método Duplo-Cego , Feminino , Fluoroquinolonas , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Estudos Prospectivos , Quinolinas/efeitos adversos , Resultado do Tratamento
6.
J Antimicrob Chemother ; 66(11): 2632-42, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21896561

RESUMO

OBJECTIVES: The primary aim of the RELIEF study was to evaluate the efficacy and safety of two sequential intravenous (iv)/oral regimens: moxifloxacin iv/oral versus piperacillin/tazobactam (TZP) iv followed by oral amoxicillin/clavulanate (AMC). PATIENTS AND METHODS: The study had a prospective, randomized, double-dummy, double-blind, multicentre design. Patients ≥18 years were prospectively stratified according to complicated skin and skin structure infection (cSSSI) subtype/diagnosis (major abscess, diabetic foot infection, wound infection or infected ischaemic ulcer), surgical intervention and severity of illness. Diagnoses and disease severity were based on predetermined criteria, documented by repeated photographs, and confirmed by an independent data review committee. Patients were randomized to receive either 400 mg of moxifloxacin iv once daily followed by 400 mg of moxifloxacin orally once daily or 4.0/0.5 g of TZP iv thrice daily followed by 875/125 mg of AMC orally twice daily for 7-21 days. The primary efficacy variable was clinical response at test of cure (TOC) for the per-protocol (PP) population. Clinical efficacy was assessed by the data review committee based on repeated photographs and case descriptions. Clinical trials registry number: NCT 00402727. RESULTS: A total of 813 patients were randomized. Clinical success rates at TOC were similar for moxifloxacin and TZP-AMC in the PP [320/361 (88.6%) versus 275/307 (89.6%), respectively; P = 0.758] and intent-to-treat (ITT) [350/426 (82.2%) versus 305/377 (80.9%), respectively; P = 0.632] populations. Thus, moxifloxacin was non-inferior to TZP-AMC. Bacteriological success rates were high in both treatment arms [moxifloxacin: 432/497 (86.9%) versus TZP-AMC: 370/429 (86.2%), microbiologically valid (MBV) population]. Moxifloxacin was non-inferior to TZP-AMC at TOC in both the MBV and the ITT populations. Both treatments were well tolerated. CONCLUSIONS: Once-daily iv/oral moxifloxacin monotherapy was clinically and bacteriologically non-inferior to iv TZP thrice daily followed by oral AMC twice daily in patients with cSSSIs.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/uso terapêutico , Compostos Aza/uso terapêutico , Quinolinas/uso terapêutico , Dermatopatias Bacterianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Compostos Aza/administração & dosagem , Compostos Aza/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fluoroquinolonas , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/efeitos adversos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/uso terapêutico , Piperacilina/administração & dosagem , Piperacilina/efeitos adversos , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Pele/microbiologia , Pele/patologia , Dermatopatias Bacterianas/microbiologia , Dermatopatias Bacterianas/patologia
7.
Lancet Infect Dis ; 20(3): 330-340, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31866328

RESUMO

BACKGROUND: Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients. METHODS: INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28-32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168. FINDINGS: Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28-32 (odds ratio 0·841, 95% CI 0·554-1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients). INTERPRETATION: Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. FUNDING: Bayer AG.


Assuntos
Administração por Inalação , Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Antibacterianos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Estudos Prospectivos , Padrão de Cuidado , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
8.
Clin Infect Dis ; 46(8): 1142-51, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18444848

RESUMO

OBJECTIVE: We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). METHODS: Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5-14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. RESULTS: After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, -12.4% to -0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, -13.8% to -3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, -6.1% to 11.5%). CONCLUSIONS: Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.


Assuntos
Ceftriaxona/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Daptomicina/uso terapêutico , Pneumonia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Ceftriaxona/efeitos adversos , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/patologia , Daptomicina/efeitos adversos , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pneumonia/patologia , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/patologia , Sepse/tratamento farmacológico , Sepse/patologia , Resultado do Tratamento
9.
J Clin Microbiol ; 46(1): 220-4, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18003803

RESUMO

We examined sequential methicillin-susceptible Staphylococcus aureus isolates from a patient with mitral valve endocarditis recovered during persistent bacteremia on standard therapy and relapse after treatment with daptomycin. An isolate obtained after 5 days of antimicrobial therapy, but before exposure to daptomycin, showed subtle physiological changes in response to daptomycin, with significant regrowth in the daptomycin killing assay compared to the treatment-naive strain. Once daptomycin was started, the population became more heterogeneous and tested as nonsusceptible. These organisms were examined in a simulated-vegetation in vitro pharmacodynamic model, which confirmed progressive decreases in killing with daptomycin concentrations that simulate those attained in humans with 6-mg/kg of body weight daily dosing. Early surgical intervention or combination therapy or both might have prevented the loss of daptomycin susceptibility.


Assuntos
Antibacterianos/farmacologia , Daptomicina/farmacologia , Farmacorresistência Bacteriana , Endocardite Bacteriana/microbiologia , Meticilina/farmacologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Bacteriemia/microbiologia , Daptomicina/farmacocinética , Daptomicina/uso terapêutico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Staphylococcus aureus/classificação , Staphylococcus aureus/isolamento & purificação
10.
J Clin Microbiol ; 46(9): 2890-6, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18596141

RESUMO

We investigated associations between the genotypic and phenotypic features of Staphylococcus aureus bloodstream isolates and the clinical characteristics of bacteremic patients enrolled in a phase III trial of S. aureus bacteremia and endocarditis. Isolates underwent pulsed-field gel electrophoresis, PCR for 33 putative virulence genes, and screening for heteroresistant glycopeptide intermediate S. aureus (hGISA). A total of 230 isolates (141 methicillin-susceptible S. aureus and 89 methicillin-resistant S. aureus [MRSA]) were analyzed. North American and European S. aureus isolates differed in their genotypic characteristics. Overall, 26% of the MRSA bloodstream isolates were USA 300 strains. Patients with USA 300 MRSA bacteremia were more likely to be injection drug users (61% versus 15%; P < 0.001), to have right-sided endocarditis (39% versus 9%; P = 0.002), and to be cured of right-sided endocarditis (100% versus 33%; P = 0.01) than patients with non-USA 300 MRSA bacteremia. Patients with persistent bacteremia were less likely to be infected with Panton-Valentine leukocidin gene (pvl)-constitutive MRSA (19% versus 56%; P = 0.005). Although 7 of 89 MRSA isolates (8%) exhibited the hGISA phenotype, no association with persistent bacteremia, daptomycin resistance, or bacterial genotype was observed. This study suggests that the virulence gene profiles of S. aureus bloodstream isolates from North America and Europe differ significantly. In this study of bloodstream isolates collected as part of a multinational randomized clinical trial, USA 300 and pvl-constitutive MRSA strains were associated with better clinical outcomes.


Assuntos
Bacteriemia/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletroforese em Gel de Campo Pulsado , Endocardite Bacteriana/microbiologia , Feminino , Genes Bacterianos , Genótipo , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase , Staphylococcus aureus/patogenicidade , Resultado do Tratamento , Virulência/genética , Adulto Jovem
12.
Diagn Microbiol Infect Dis ; 89(2): 151-157, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28793964

RESUMO

Clinical isolates of Staphylococcus aureus (n=3929) collected by 54 medical center laboratories in 12 countries in 2014-2016 were tested for in vitro susceptibility to tedizolid, linezolid, and 11 comparators using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology with minimum inhibitory concentrations (MICs) interpreted by CLSI M100-S26 (2016) criteria. All isolates of S. aureus tested were susceptible to both tedizolid (MIC, ≤0.5µg/mL) and linezolid (MIC, ≤4µg/mL). The concentration of tedizolid that inhibited 90% of isolates (MIC90) was 0.5µg/mL, 4-fold lower than linezolid (MIC90, 2µg/mL). Tedizolid MIC frequency distributions were equivalent for methicillin-susceptible (MSSA; n=2090; MIC90, 0.25µg/mL) and methicillin-resistant (MRSA; n=1839; MIC90, 0.25µg/mL) S. aureus. We conclude that tedizolid possesses more potent in vitro activity than linezolid against recently collected isolates of S. aureus, including isolates of MRSA, and that resistance to currently marketed oxazolidinones (tedizolid and linezolid) remains very uncommon.


Assuntos
Antibacterianos/farmacologia , Linezolida/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Organofosfatos/farmacologia , Oxazóis/farmacologia , Humanos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia
13.
Int J Antimicrob Agents ; 28(5): 385-8, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17046205

RESUMO

An initiative was taken to determine the in vitro activity of daptomycin against 85 Gram-positive isolates with reduced susceptibilities to linezolid and quinupristin/dalfopristin. Daptomycin had potent activity against all strains, with a Staphylococcus spp. minimum inhibitory concentration (MIC) < or =2 microg/mL and an Enterococcus spp. MIC < or =8 microg/mL. Resistance to linezolid and quinupristin/dalfopristin appears to be independent of reduced susceptibility to daptomycin.


Assuntos
Acetamidas/farmacologia , Daptomicina/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Oxazolidinonas/farmacologia , Virginiamicina/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Humanos , Linezolida , Staphylococcus aureus/efeitos dos fármacos
14.
BMJ Open Respir Res ; 2(1): e000100, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26688732

RESUMO

BACKGROUND: Treatment of infective bronchitis involving Pseudomonas aeruginosa is a cornerstone of care in patients with cystic fibrosis (CF). This phase IIb, randomised, double-blind, placebo-controlled study assessed the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in this population. METHODS: Patients with CF, ≥12 years of age (N=286), were randomised to ciprofloxacin DPI (32.5 mg (n=93) or 48.75 mg (n=93)), or corresponding placebo (32.5 mg, n=65; 48.75 mg, n=35) twice daily for 28 days. The primary objective was the change in forced expiratory volume in 1 s (FEV1) from baseline (day 0) to end of treatment (day 29) in the intent-to-treat population for ciprofloxacin DPI compared with the corresponding placebo group. RESULTS: The primary effectiveness objective was not met; there were no significant differences in change in FEV1 between ciprofloxacin DPI and the corresponding placebo group for either dose (p=0.154). However, in pooled analyses, FEV1 decline from baseline to treatment end was significantly lower with ciprofloxacin DPI than with placebo (pooled data; p=0.02). Ciprofloxacin DPI showed positive effects on sputum bacterial load and quality of life, but these effects were not maintained at the 4-week follow-up. Ciprofloxacin DPI was well tolerated and there were no significant differences in type/incidence of treatment-emergent adverse events by treatment group (p=0.115). CONCLUSIONS: Further investigations are needed to determine the full scope of the beneficial effects of ciprofloxacin DPI for patients with CF. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00645788; EudraCT 2008-008314-40.

16.
Lancet Infect Dis ; 13(3): 269-75, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23332713

RESUMO

To bring new antibacterial drugs to the market is challenging because discovery of new agents is difficult, two large trials per indication are needed in accordance with traditional regulatory requirements, and the economic reward is limited if the use of new antibiotics is constrained. These challenges have resulted in an alarmingly thin antibiotic pipeline, despite the rapid and continued growth in the need for new drugs. Approaches that balance the quantity of data needed for registration with the unmet medical need would encourage work in this area. Therefore, a tiered regulatory framework that allows either disease-based or pathogen-based label indications is proposed, with label wording that promotes the most appropriate use of new agents. Such a framework is within the bounds of present regulatory approaches, is amenable to international harmonisation, and would be a welcome step towards the facilitation of a robust and sustainable discovery and development infrastructure.


Assuntos
Antibacterianos , Aprovação de Drogas/legislação & jurisprudência , Avaliação de Medicamentos , Antibacterianos/farmacologia , Ensaios Clínicos como Assunto , Farmacorresistência Bacteriana , Humanos , Avaliação das Necessidades , Estados Unidos
19.
Antimicrob Agents Chemother ; 51(12): 4255-60, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17923487

RESUMO

Most antibiotics with bactericidal activity require that the bacteria be actively dividing to produce rapid killing. However, in many infections, such as endocarditis, prosthetic joint infections, and infected embedded catheters, the bacteria divide slowly or not at all. Daptomycin is a lipopeptide antibiotic with a distinct mechanism of action that targets the cytoplasmic membrane of gram-positive organisms, including Staphylococcus aureus. Daptomycin is rapidly bactericidal against exponentially growing bacteria (a 3-log reduction in 60 min). The objectives of this study were to determine if daptomycin is bactericidal against nondividing S. aureus and to quantify the extent of the bactericidal activity. In high-inoculum methicillin-sensitive S. aureus cultures in stationary phase (10(10) CFU/ml), daptomycin displayed concentration-dependent bactericidal activity, requiring 32 micro/ml to achieve a 3-log reduction. In a study comparing several antibiotics at 100 microg/ml, daptomycin demonstrated faster bactericidal activity than nafcillin, ciprofloxacin, gentamicin, and vancomycin. In experiments where bacterial cell growth was halted by the metabolic inhibitor carbonyl cyanide m-chlorophenylhydrazone or erythromycin, daptomycin (10 microg/ml) achieved the bactericidal end point (a 3-log reduction) within 2 h. In contrast, ciprofloxacin (10 microg/ml) did not produce bactericidal activity. Daptomycin (2 microg/ml) remained bactericidal against cold-arrested S. aureus, which was protected from the actions of ciprofloxacin and nafcillin. The data presented here suggest that, in contrast to that of other classes of antibiotics, the bactericidal activity of daptomycin does not require cell division or active metabolism, most likely as a consequence of its direct action on the bacterial membrane.


Assuntos
Daptomicina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Divisão Celular/efeitos dos fármacos , Ciprofloxacina/farmacologia , Eritromicina/farmacologia , Gentamicinas/farmacologia , Hidrazonas/farmacologia , Testes de Sensibilidade Microbiana , Nafcilina/farmacologia , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/metabolismo , Vancomicina/farmacologia
20.
Antimicrob Agents Chemother ; 51(5): 1787-94, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17307984

RESUMO

The rising rates of antibiotic resistance accentuate the critical need for new antibiotics. Daptomycin is a new antibiotic with a unique mode of action and a rapid in vitro bactericidal effect against gram-positive organisms. This study examined the kinetics of daptomycin's bactericidal action against peritonitis caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in healthy and neutropenic mice and compared this activity with those of other commonly used antibiotics. CD-1 mice were inoculated intraperitoneally with lethal doses of MSSA (Xen-29) or MRSA (Xen-1), laboratory strains transformed with a plasmid containing the lux operon, which confers bioluminescence. One hour later, the animals were given a single dose of daptomycin at 50 mg/kg of body weight subcutaneously (s.c.), nafcillin at 100 mg/kg s.c., vancomycin at 100 mg/kg s.c., linezolid at 100 mg/kg via gavage (orally), or saline (10 ml/kg s.c.). The mice were anesthetized hourly, and photon emissions from living bioluminescent bacteria were imaged and quantified. The luminescence in saline-treated control mice either increased (neutropenic mice) or remained relatively unchanged (healthy mice). In contrast, by 2 to 3 h postdosing, daptomycin effected a 90% reduction of luminescence of MSSA or MRSA in both healthy and neutropenic mice. The activity of daptomycin against both MSSA and MRSA strains was superior to those of nafcillin, vancomycin, and linezolid. Against MSSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than nafcillin or linezolid. Against MRSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than vancomycin or linezolid. The rapid decrease in the luminescent signal in the daptomycin-treated neutropenic mice underscores the potency of this antibiotic against S. aureus in the immune-suppressed host.


Assuntos
Antibacterianos/farmacologia , Daptomicina/farmacologia , Resistência a Meticilina , Peritonite/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Acetamidas/farmacologia , Animais , Contagem de Colônia Microbiana , Daptomicina/uso terapêutico , Feminino , Linezolida , Medições Luminescentes , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Oxazolidinonas/farmacologia
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