RESUMO
BACKGROUND: Ceftolozane/tazobactam, a cephalosporin-ß-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed. METHODS: This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points. RESULTS: The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol. CONCLUSION: Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.
Assuntos
Infecções Intra-Abdominais , Metronidazol , Adulto , Humanos , Criança , Meropeném/efeitos adversos , Metronidazol/efeitos adversos , Antibacterianos/efeitos adversos , Ácido Penicilânico/efeitos adversos , Cefalosporinas/efeitos adversos , Tazobactam/efeitos adversos , Infecções Intra-Abdominais/tratamento farmacológico , Escherichia coliRESUMO
BACKGROUND: Ceftolozane/tazobactam, a cephalosporin-ß-lactamase inhibitor combination, active against multidrug-resistant Gram-negative pathogens, is approved for treatment of adults with complicated urinary tract infections (cUTI). Safety and efficacy of ceftolozane/tazobactam in pediatric participants with cUTI, including pyelonephritis, were assessed. METHODS: This phase 2 study (NCT03230838) compared ceftolozane/tazobactam with meropenem for treatment of cUTI in participants from birth to <18 years of age. The primary objective was safety and tolerability. Key secondary end points included clinical cure and per-participant microbiologic response rates at end of treatment (EOT) and test of cure (TOC) visits. RESULTS: The microbiologic modified intent-to-treat (mMITT) population included 95 participants (ceftolozane/tazobactam, n = 71; meropenem, n = 24). The most common diagnosis and pathogen were pyelonephritis (ceftolozane/tazobactam, 84.5%; meropenem, 79.2%) and Escherichia coli (ceftolozane/tazobactam, 74.6%; meropenem, 87.5%); 5.7% (ceftolozane/tazobactam) and 4.8% (meropenem) of E. coli isolates were extended-spectrum ß-lactamase-producers. Rates of adverse events were similar between treatment groups (any: ceftolozane/tazobactam, 59.0% vs. meropenem, 60.6%; drug-related: ceftolozane/tazobactam, 14.0% vs. meropenem, 15.2%; serious: ceftolozane/tazobactam, 3.0% vs. meropenem, 6.1%). Rates of clinical cure for ceftolozane/tazobactam and meropenem at EOT were 94.4% and 100% and at TOC were 88.7% and 95.8%, respectively. Rates of microbiologic eradication for ceftolozane/tazobactam and meropenem at EOT were 93.0% and 95.8%, and at TOC were 84.5% and 87.5%, respectively. CONCLUSIONS: Ceftolozane/tazobactam had a favorable safety profile in pediatric participants with cUTI; rates of clinical cure and microbiologic eradication were high and similar to meropenem. Ceftolozane/tazobactam is a safe and effective new treatment option for children with cUTI, especially due to antibacterial-resistant Gram-negative pathogens.
Assuntos
Pielonefrite , Infecções Urinárias , Adulto , Recém-Nascido , Humanos , Criança , Meropeném/efeitos adversos , Escherichia coli , Ácido Penicilânico/efeitos adversos , Cefalosporinas/efeitos adversos , Tazobactam/efeitos adversos , Antibacterianos/efeitos adversos , Infecções Urinárias/tratamento farmacológico , Pielonefrite/tratamento farmacológicoRESUMO
OBJECTIVES: This study aimed to evaluate the efficacy and safety of ceftolozane/tazobactam (C/T) plus metronidazole versus meropenem plus placebo for the treatment of complicated intra-abdominal infection (cIAI) in Chinese adult participants. METHODS: In this phase III clinical trial (NCT03830333), Chinese adult participants with cIAI were randomized 1:1 to receive C/T plus metronidazole or meropenem plus placebo. The primary objective was to assess C/T plus metronidazole for noninferiority versus meropenem for clinical response rate at the test of cure (TOC; 28 ± 2 days after study start) visit in the clinically evaluable population. Secondary endpoints included clinical and microbiologic responses at the TOC and end-of-treatment (≤24 hours after last dose) visits and adverse event rates. RESULTS: Clinical cure at the TOC visit in the clinically evaluable population was 95.2% and 93.1% for C/T plus metronidazole and meropenem, respectively (between-treatment difference: 2.1% [95% confidence interval: -4.7%, 8.8%]); thus, noninferiority was met. Clinical responses at the TOC and end-of-treatment visits and microbiologic responses at the TOC visit were consistent with the primary efficacy endpoint. Safety was comparable between study treatment groups. CONCLUSION: In Chinese adult participants with cIAI, C/T plus metronidazole was noninferior to meropenem, with comparable safety.
Assuntos
Infecções Intra-Abdominais , Metronidazol , Adulto , Antibacterianos/efeitos adversos , Cefalosporinas/efeitos adversos , China , Método Duplo-Cego , Humanos , Infecções Intra-Abdominais/tratamento farmacológico , Meropeném/efeitos adversos , Metronidazol/efeitos adversos , Tazobactam/efeitos adversosRESUMO
BACKGROUND: We prospectively evaluated efficacy and safety of daptomycin versus active comparator in children with acute hematogenous osteomyelitis (AHO). METHODS: Randomized, controlled, double-blind, global, multicenter, phase 3 trial. Patients 1-17 years of age with suspected/confirmed AHO requiring hospitalization and intravenous therapy were randomized 1:1 to intravenous daptomycin (once-daily, age-adjusted doses) or comparator (vancomycin, nafcillin or equivalent) ≥4 days, followed by oral therapy (14-42 days total). Primary endpoint: protocol-defined clinical improvement by Day 5 in the modified intention-to-treat (MITT) population (confirmed AHO, ≥1 dose of study treatment); differences between study arms were evaluated using a prespecified 15% noninferiority margin for daptomycin. RESULTS: Seventy-three patients per arm received treatment. Pathogens were isolated from 62% of patients (83% methicillin-susceptible Staphylococcus aureus, 9% methicillin-resistant S. aureus [MRSA]). Clinical improvement by Day 5 was observed in 55/71 (78%) daptomycin- and 58/70 (83%) comparator-treated MITT patients (95% confidence interval [CI]: -19.4, 7.4). This difference was not statistically significant; however, daptomycin did not meet the prespecified 15% noninferiority margin, since the lower bound of the 95% CI extended below 15%. Overall, 82% of daptomycin and 87% of comparator patients achieved clinical cure at the test-of-cure visit (secondary endpoint). More comparator patients had treatment-emergent (63% vs. 46%) and treatment-related (18% vs. 7%) adverse events. CONCLUSIONS: Differences between daptomycin and comparator for the primary endpoint were not statistically significant; however, prespecified noninferiority criteria for daptomycin were not met. With insufficient cases of confirmed MRSA, we could not evaluate daptomycin for MRSA AHO. Our nonvalidated protocol design yields valuable information for implementing future trials in AHO (ClinicalTrials.gov NCT01922011).
Assuntos
Antibacterianos/uso terapêutico , Daptomicina/uso terapêutico , Osteomielite/sangue , Osteomielite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Doença Aguda/terapia , Administração Intravenosa , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Lactente , Testes de Sensibilidade Microbiana , Osteomielite/microbiologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
We evaluated the microbiological efficacy of tedizolid compared with that of linezolid against common and emerging pathogens using pooled data from 2 phase 3 trials (NCT01170221 and NCT01421511) in patients with acute bacterial skin and skin structure infections. Patients received tedizolid 200â¯mg once daily for 6â¯days (nâ¯=â¯664) or linezolid 600â¯mg twice daily for 10â¯days (nâ¯=â¯669). Favorable microbiological outcome in both treatment groups, defined as eradication or presumed eradication at the end of treatment and at the posttherapy evaluation, exceeded 85% for most pathogens, including methicillin-resistant Staphylococcus aureus. Favorable microbiological response was observed for staphylococci and streptococci at tedizolid minimal inhibitory concentration values ≤0.5â¯mg/L and 0.25â¯mg/L, respectively. The studies demonstrated positive microbiological outcomes against common pathogens with a 6-day, once-daily regimen of tedizolid phosphate in patients with acute bacterial skin and skin structure infections.
Assuntos
Antibacterianos/administração & dosagem , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Linezolida/administração & dosagem , Oxazolidinonas/administração & dosagem , Dermatopatias Bacterianas/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Tetrazóis/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
Staphylococcus lugdunensis and Staphylococcus haemolyticus are unique among CoNS in that the former often causes aggressive disease, while the latter consistently exhibits high rates of multidrug resistance. We evaluated the in vitro susceptibility of contemporary (2012-2013) isolates from both pathogens to tedizolid and comparators, using standard methodology. Results were interpreted using CLSI and EUCAST breakpoints. Overall, 106 S. lugdunensis and 103 S. haemolyticus isolates were collected from 51 medical centers in the United States and 30 centers in 18 European countries. Tedizolid showed good activity against S. lugdunensis (MIC50/MIC90: 0.12/0.12â¯mg/L) and S. haemolyticus (MIC50/MIC90: 0.12/0.12â¯mg/L), inhibiting all isolates at MIC ≤0.25â¯mg/L. Based on the EUCAST breakpoint for staphylococci and when substituting the CLSI breakpoint for Staphylococcus aureus, all isolates were tedizolid susceptible. All isolates were also susceptible to linezolid, but the in vitro potency of tedizolid was 4-fold greater than that of linezolid against both S. lugdunensis and S. haemolyticus, based on MIC90 values. S. lugdunensis exhibited ≥99% susceptibility to vancomycin, teicoplanin, gentamicin, levofloxacin, and trimethoprim-sulfamethoxazole; 7% of isolates were resistant to tetracycline, 11% to clindamycin, and 2% were methicillin-resistant. S. haemolyticus exhibited high rates of resistance to commonly used anti-staphylococcal agents: 71% of isolates were resistant to methicillin, 36%-37% to clindamycin, and 30%-50% to gentamicin. These in vitro findings suggest that tedizolid could be an alternative treatment option for infections due to these medically important CoNS pathogens. Additional clinical evaluation and continued surveillance of tedizolid in vitro activity against S. lugdunensis and S. haemolyticus are warranted.
Assuntos
Antibacterianos/farmacologia , Oxazolidinonas/farmacologia , Staphylococcus haemolyticus/efeitos dos fármacos , Staphylococcus lugdunensis/efeitos dos fármacos , Tetrazóis/farmacologia , Coagulase/deficiência , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana/normas , Viabilidade Microbiana/efeitos dos fármacos , Infecções Estafilocócicas/microbiologia , Staphylococcus haemolyticus/isolamento & purificação , Staphylococcus lugdunensis/isolamento & purificaçãoRESUMO
BACKGROUND: Staphylococcus aureus, including community-associated methicillin-resistant S. aureus, is an important cause of pediatric bacteremia. Daptomycin is a well-established treatment option for Gram-positive bacteremia in adults, but its safety and efficacy in children require confirmation. METHODS: This was a randomized (2:1), evaluator-blinded, multicenter, phase 4 clinical trial comparing intravenous daptomycin with standard-of-care (SOC) for treatment of S. aureus bacteremia in 1- to 17-year-old patients (Clinicaltrials.gov: NCT01728376). Total treatment duration (intravenous followed by oral step-down therapy) was 5-42 days. Daptomycin was dosed once daily by patient age: 12-17 years, 7 mg/kg; 7-11 years, 9 mg/kg and 1-6 years, 12 mg/kg. The primary objective was to evaluate daptomycin safety in children who received ≥1 dose; secondary objectives included comparing daptomycin efficacy with SOC (the trial was not designed to confirm noninferiority) and pharmacokinetic analysis. RESULTS: Fifty-five children were randomized to daptomycin and 27 to SOC (primarily vancomycin or cefazolin); 90% had S. aureus. In both groups, 15% of patients had drug-related adverse events, primarily diarrhea (4% daptomycin, 8% SOC) and increased creatine phosphokinase (4% daptomycin, 0% SOC). Clinical success (blinded evaluator-assessed complete/partial resolution of bacteremia signs and symptoms 7-14 days after end-of-treatment) rates were similar for daptomycin (88%) and SOC (77%; 95% confidence interval for difference: -9% to 31%). Daptomycin plasma levels across age groups were comparable with those in adults receiving daptomycin at 6 mg/kg. CONCLUSIONS: Once-daily, age-appropriate daptomycin was well tolerated in children with staphylococcal bacteremia; efficacy was comparable with SOC. Daptomycin in age-adjusted doses is a safe treatment alternative in this setting.
Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Daptomicina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Administração Intravenosa , Adolescente , Antibacterianos/efeitos adversos , Criança , Pré-Escolar , Daptomicina/efeitos adversos , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Resultado do TratamentoRESUMO
For effective antibacterial therapy, physicians require qualitative test results using susceptibility breakpoints provided by clinical microbiology laboratories. This article summarizes the key components used to establish the Clinical Laboratory Standards Institute (CLSI) breakpoints for tedizolid. First, in vitro studies using recent surveillance and clinical trial isolates ascertained minimal inhibitory concentration (MIC) distributions against pertinent organisms, including staphylococci, streptococci, and enterococci. Studies in animal models of infection determined rates of antibacterial efficacy and survival following administration of tedizolid phosphate at doses equivalent to those in humans. Pharmacokinetic and pharmacodynamic analyses examined the relationship between plasma concentrations and MICs against the target organism. Finally, clinical trials assessed clinical and microbiologic outcomes by MIC. All these data were evaluated and combined to obtain the ratified CLSI susceptibility criteria for tedizolid of ≤0.5µg/mL for Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Enterococcus faecalis and ≤0.25µg/mL for Streptococcus anginosus group.
Assuntos
Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Linezolida/farmacologia , Oxazolidinonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Streptococcus agalactiae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Carga Bacteriana/efeitos dos fármacos , Enterococcus faecalis/isolamento & purificação , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/isolamento & purificação , Streptococcus agalactiae/isolamento & purificação , Streptococcus pyogenes/isolamento & purificaçãoRESUMO
In vitro activity of tedizolid and comparators against 11,231 Gram-positive clinical isolates from the United States (84 centers) and Europe (115 centers) were summarized as part of the Surveillance of Tedizolid Activity and Resistance program between 2009 and 2013. Susceptibility testing was performed according to Clinical Laboratory and Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing criteria. Tedizolid inhibited 99.7% of all isolates at MIC ≤0.5 mg/L; activity was similar regardless of methicillin or vancomycin resistance phenotypes of Staphylococcus aureus and enterococci, respectively. Tedizolid MIC >1 mg/L was reported for 3 S. aureus, 4 coagulase-negative staphylococci, and 2 enterococcal isolates; all streptococci were inhibited at MIC ≤0.5 mg/L. Tedizolid was ≥4-fold more potent than linezolid against all groups, including resistant phenotypes. Tedizolid had potent/stable activity against a large, contemporary collection of Gram-positive clinical isolates, with low rates of resistance.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Organofosfatos/farmacologia , Oxazóis/farmacologia , Monitoramento Epidemiológico , Europa (Continente)/epidemiologia , Bactérias Gram-Positivas/isolamento & purificação , Infecções por Bactérias Gram-Positivas/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Tedizolid is a novel oxazolidinone antibacterial with potent activity against a wide range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although tedizolid is approved by the US Food and Drug Administration (FDA) for treatment of patients with acute bacterial skin and skin structure infection, commercial susceptibility testing products for tedizolid are not currently available. This study evaluated the usefulness of applying linezolid susceptibility test results as a surrogate for predicting susceptibility to tedizolid in clinically significant Gram-positive pathogens. METHODS: Gram-positive isolates (N = 10,702) were obtained from annual surveillance programs conducted between 2009 and 2012, from 3 tedizolid clinical trials, and from a preclinical study of the antibacterial activity of tedizolid. Susceptibility testing of linezolid and tedizolid was performed using the reference broth microdilution method in accordance with Clinical and Laboratory Standards Institute methods. RESULTS: The minimum inhibitory concentration (MIC) distribution for tedizolid and linezolid against this set of isolates was consistent with that of previous reports. Scatter plot analysis of relevant subsets of organisms was performed and showed high categorical agreement between linezolid and tedizolid MIC results (>99% for staphylococci and streptococci; >98% for enterococci). Very major error rates (ie, tedizolid false-susceptible errors) were very low and within acceptable limits for a surrogate agent: S. aureus and other staphylococcal species, 0%; Enterococcus spp, 0.2%; and Streptococcus spp, 0%. CONCLUSIONS: High categorical agreement between MIC values for tedizolid and linezolid and low very major error rates were shown for all organism groups tested, supporting the use of linezolid as a reliable surrogate for tedizolid susceptibility testing.
Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Organofosfatos/farmacologia , Oxazóis/farmacologia , Oxazolidinonas/farmacologia , Biomarcadores , Erros de Diagnóstico/estatística & dados numéricos , Humanos , Linezolida , Testes de Sensibilidade Microbiana/métodosRESUMO
Immunization with the Ixodes scapularis protein, subolesin, has previously been shown to protect hosts against tick infestation and to decrease acquisition of Anaplsma marginale and Babesia bigemina. Here we report the efficacy of subolesin, a conserved tick protein that can act as a regulator of gene expression, expressed from vaccinia virus for use as an orally delivered reservoir - targeted vaccine for prevention of tick infestation and acquisition/transmission of Borrelia burgdorferi to its tick and mouse hosts. We cloned subolesin into vaccinia virus and showed that it is expressed from mammalian cells infected with the recombinant virus in vitro. We then vaccinated mice by oral gavage. A single dose of the vaccine was sufficient for mice to generate antibody response to subolesin. Vaccination with the subolesin expressing vaccinia virus inhibited tick infestation by 52% compared to control vaccination with vaccinia virus and reduced uptake of B. burgdorferi among the surviving ticks that fed to repletion by 34%. There was a reduction in transmission of B. burgdorferi to uninfected vaccinated mice of 40% compared to controls. These results suggest that subolesin has potential as a component of a reservoir targeted vaccine to decrease B. burgdorferi, Babesia and Anaplasma species infections in their natural hosts.
Assuntos
Antígenos/imunologia , Proteínas de Artrópodes/imunologia , Vacinas Bacterianas/imunologia , Borrelia burgdorferi/patogenicidade , Ixodes/microbiologia , Doença de Lyme/prevenção & controle , Animais , Anticorpos Antibacterianos/sangue , Antígenos/genética , Proteínas de Artrópodes/genética , Feminino , Ixodes/imunologia , Doença de Lyme/transmissão , Camundongos , Camundongos Endogâmicos C3H , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Infestações por Carrapato/prevenção & controle , Vacinação , Vaccinia virus/genética , Vaccinia virus/imunologiaRESUMO
The plant-associated bacterium Pseudomonas syringae pv. syringae simultaneously produces two classes of metabolites: the small cyclic lipodepsinonapeptides such as the syringomycins and the larger cyclic lipodepsipeptide syringopeptins SP22 or SP25. The syringomycins inhibit a broad spectrum of fungi (but particularly yeasts) by lipid-dependent membrane interaction. The syringopeptins are phytotoxic and inhibitory to Gram-positive bacteria. In this study, the fungicidal activities of two major syringopeptins, SP22A and SP25A, and their mechanisms of action were investigated and compared to those of syringomycin E. SP22A and SP25A were observed to inhibit the fungal yeasts Saccharomyces cerevisiae and Candida albicans although less effectively than syringomycin E. S. cerevisiae mutants defective in ergosterol and sphingolipid biosyntheses were less susceptible to SP22A and SP25A but the relative inhibitory capabilities of SRE vs. SP22A and SP25A were maintained. Similar differences were observed for capabilities to cause cellular K(+) and Ca(2+) fluxes in S. cerevisiae. Interestingly, in phospholipid bilayers the syringopeptins are found to induce larger macroscopic ionic conductances than syringomycin E but form single channels with similar properties. These findings suggest that the syringopeptins target the yeast plasma membrane, and, like syringomycin E, employ a lipid-dependent channel-forming mechanism of action. The differing degrees of growth inhibition by these lipodepsipeptides may be explained by differences in their hydrophobicities. The more hydrophobic SP22A and SP25A might interact more strongly with the yeast cell wall that would create a selective barrier for their incorporation into the plasma membrane.
RESUMO
Lyme disease is a major human health problem which continues to increase in incidence and geographic distribution. As a vector-borne zoonotic disease, Lyme disease may be amenable to reservoir targeted strategies for control. We have previously reported that a vaccinia virus (VV) based vaccine expressing outer surface protein A (OspA) of Borrelia burgdorferi, the causative agent of Lyme disease, protects inbred strains of laboratory mice against infection by feeding ticks and clears the ticks of infection when administered by gavage. Here we extend these studies to develop an effective bait formulation for delivery of the VV based vaccine and test its characteristics under simulated environmental conditions. We show that this vaccine is efficacious in decreasing acquisition of B. burgdorferi by uninfected larval ticks as well as in decreasing transmission from infected ticks to its natural reservoir, Peromyscus leucopus, when fed to mice in oral baits. Using live, in vivo imaging techniques, we describe the distribution of vaccinia virus infection after ingestion of the baited vaccines and establish the use of in vivo imaging technology for optimization of bait delivery. In summary, a VV based OspA vaccine is stable in an oral bait preparation and provides protection against infection for both the natural reservoir and the tick vector of Lyme disease.
Assuntos
Reservatórios de Doenças , Transmissão de Doença Infecciosa/prevenção & controle , Vacinas contra Doença de Lyme/imunologia , Doença de Lyme/prevenção & controle , Vacinação/métodos , Zoonoses/transmissão , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/genética , Vacinas Bacterianas/imunologia , Borrelia burgdorferi/genética , Borrelia burgdorferi/imunologia , Química Farmacêutica , Portadores de Fármacos , Vetores Genéticos , Larva/imunologia , Lipoproteínas/genética , Lipoproteínas/imunologia , Doença de Lyme/imunologia , Vacinas contra Doença de Lyme/administração & dosagem , Vacinas contra Doença de Lyme/genética , Camundongos , Camundongos Endogâmicos BALB C , Peromyscus/imunologia , Carrapatos/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vaccinia virus/genéticaRESUMO
Many Actinomycetes aminoglycosides are widely used antibiotics. Although mainly antibacterials, a few known aminoglycosides also inhibit yeasts, protozoans and important crop pathogenic fungal oomycetes. Here we show that attachment of a C8 alkyl chain to ring III of a neamine-based aminoglycoside specifically at the 4â³-o position yields a broad-spectrum fungicide (FG08) without the antibacterial properties typical for aminoglycosides. Leaf infection assays and greenhouse studies show that FG08 is capable of suppressing wheat fungal infections by Fusarium graminearum-the causative agent of Fusarium head blight-at concentrations that are minimally phytotoxic. Unlike typical aminoglycoside action of ribosomal protein translation miscoding, FG08's antifungal action involves perturbation of the plasma membrane. This antibacterial to antifungal transformation could pave the way for the development of a new class of aminoglycoside-based fungicides suitable for use in crop disease applications. In addition, this strategy is an example of reviving a clinically obsolete drug by simple chemical modification to yield a new application.
Assuntos
Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Fusarium/efeitos dos fármacos , Canamicina/análogos & derivados , Trissacarídeos/farmacologia , Aminoglicosídeos/química , Aminoglicosídeos/toxicidade , Antibacterianos/química , Antifúngicos/química , Antifúngicos/toxicidade , Membrana Celular/efeitos dos fármacos , Produtos Agrícolas/microbiologia , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Fungicidas Industriais/toxicidade , Canamicina/farmacologia , Doenças das Plantas/microbiologia , Folhas de Planta , Trissacarídeos/química , Trissacarídeos/toxicidade , Triticum/microbiologiaRESUMO
A library of 5''-modified neomycin derivatives were synthesized for an antibacterial structure-activity optimization strategy. Two leads exhibited prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clinically used antibiotics. Significant synergistic activities were observed, which may lead to the development of novel therapeutic practices in the battle against infectious bacteria.
Assuntos
Antibacterianos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Neomicina , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Enterococcus/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Neomicina/análogos & derivados , Neomicina/síntese química , Neomicina/química , Neomicina/farmacologia , Relação Estrutura-Atividade , Resistência a VancomicinaRESUMO
The Pseudomonas syringae syringopeptins are cationic cyclic lipodepsipeptides that inhibit fungi and bacteria. The homolog syringopeptin (SP)25A was strongly inhibitory to several Gram-positive bacteria with minimum inhibitory concentrations ranging between 1.95 and 7.8 microg mL(-1). In contrast, it was not inhibitory to several Gram-negative bacteria. At 5 and 10 microg mL(-1), SP25A rapidly inhibited the growth of Bacillus subtilis and was bacteriocidal. Teichoic acid D-alanylation dltB- and dltD-defective mutant strains of B. subtilis were more susceptible to SP25A compared with the parental wild-type strain. The degree of susceptibility of the parent strain, but not the dltB and dltD mutant strains, increased at alkaline pH (9.0). In contrast, the parental and mutant strains had the same susceptibilities to syringopeptins SP22A and SP508A at pH 7.0 and 9.0. These results suggest that the cell wall anionic teichoic acids modulate SP25A action against B. subtilis, and they provide an explanation for the selective inhibition of Gram-positive bacteria by SP25A.
Assuntos
Alanina/metabolismo , Toxinas Bacterianas/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Ácidos Teicoicos/metabolismo , Sequência de Aminoácidos , Bactérias Gram-Positivas/genética , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificaçãoAssuntos
Anti-Infecciosos/síntese química , Carboidratos/síntese química , Oxazolidinonas/síntese química , Anti-Infecciosos/farmacologia , Carboidratos/farmacologia , Técnicas de Química Combinatória/métodos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Oxazolidinonas/farmacologia , Rhodotorula/efeitos dos fármacos , Sonicação , Staphylococcus aureus/efeitos dos fármacosRESUMO
The syringopeptins are a group of antimicrobial cyclic lipodepsipeptides produced by several plant-associated pseudomonads. A novel syringopeptin, SP508, was shown to be produced as two homologs (A and B) by Pseudomonas syringae pv. lachrymans strain 508 from apple and to structurally resemble syringopeptin SP22. SP508 differed from SP22 and other syringopeptins by having three instead of four alpha,beta-unsaturated amino acids and a longer beta-hydroxy acyl chain. Both SP508 and SP22 displayed growth-inhibitory activities against Mycobacterium smegmatis, other gram-positive bacteria, and yeasts but not against gram-negative bacteria. Structure-activity analyses of the SP508 and SP22 homologs indicated chemical structural features that lead to enhanced antimycobacterial activity by these pseudomonad cyclic lipodepsipeptides.
Assuntos
Anti-Infecciosos/farmacologia , Depsipeptídeos/farmacologia , Lipoproteínas/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Pseudomonas syringae/química , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/química , Peptídeos Cíclicos/genéticaRESUMO
The synthesis of a library of trehalose-based compounds has been accomplished, and their activities against Mycobacterium smegmatis have been determined. A preliminary structure-activity relationship (SAR) is reported. Despite not having a potent lead, one of the trehalose derivatives displays strong activity when applied with isoniazid (INH), which is known to have low sterilizing activity. The bacteriocidal nature of our compounds against Mycobacterium may be significant for the development of new therapies against tuberculosis.
Assuntos
Mycobacterium smegmatis/efeitos dos fármacos , Trealose/síntese química , Trealose/farmacologia , Técnicas de Química Combinatória , Relação Dose-Resposta a Droga , Isoniazida , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Trealose/químicaRESUMO
A divergent approach was employed for the synthesis of aminosugars, from which a novel library of aminoglycoside antibiotics (pyranmycins) was synthesized. Pyranmycins have comparable antibacterial activity as neomycin, a clinically used aminoglycoside antibiotic, against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Mycobacterium smegmatis. In addition, pyranmycins, like streptomycin, are bacteriocidal while isoniazid (INH) is bacteriostatic. Therefore, pyranmycins may provide new therapeutic options in the treatment against tuberculosis. Several members of pyranmycins also manifest modest anti-Tat and anti-Rev activities, which may aid in the development of new anti-HIV agents. Although the antibacterial activity of pyranmycins against aminoglycoside resistant bacteria is less than expected, the synthetic methodologies of utilizing a library of aminosugars can be a model for future studies of glycodiversification or glycorandomization.