RESUMO
Escherichia coli is commonly involved in infections with a heavy bacterial burden. Piperacillin-tazobactam and carbapenems are among the recommended empirical treatments for health care-associated complicated intra-abdominal infections. In contrast to amoxicillin-clavulanate, both have reduced in vitro activity in the presence of high concentrations of extended-spectrum ß-lactamase (ESBL)-producing and non-ESBL-producing E. coli bacteria. Our goal was to compare the efficacy of these antimicrobials against different concentrations of two clinical E. coli strains, one an ESBL-producer and the other a non-ESBL-producer, in a murine sepsis model. An experimental sepsis model {~5.5 log10 CFU/g [low inoculum concentration (LI)] or ~7.5 log(10) CFU/g [high inoculum concentration (HI)]} using E. coli strains ATCC 25922 (non-ESBL producer) and Ec1062 (CTX-M-14 producer), which are susceptible to the three antimicrobials, was used. Amoxicillin-clavulanate (50/12.5 mg/kg given intramuscularly [i.m.]), piperacillin-tazobactam (25/3.125 mg/kg given intraperitoneally [i.p.]), and imipenem (30 mg/kg i.m.) were used. Piperacillin-tazobactam and imipenem reduced spleen ATCC 25922 strain concentrations (-2.53 and -2.14 log10 CFU/g [P < 0.05, respectively]) in the HI versus LI groups, while amoxicillin-clavulanate maintained its efficacy (-1.01 log10 CFU/g [no statistically significant difference]). Regarding the Ec1062 strain, the antimicrobials showed lower efficacy in the HI than in the LI groups: -0.73, -1.89, and -1.62 log10 CFU/g (P < 0.05, for piperacillin-tazobactam, imipenem, and amoxicillin-clavulanate, respectively, although imipenem and amoxicillin-clavulanate were more efficacious than piperacillin-tazobactam). An adapted imipenem treatment (based on the time for which the serum drug concentration remained above the MIC obtained with a HI of the ATCC 25922 strain) improved its efficacy to -1.67 log10 CFU/g (P < 0.05). These results suggest that amoxicillin-clavulanate could be an alternative to imipenem treatment of infections caused by ESBL- and non-ESBL-producing E. coli strains in patients with therapeutic failure with piperacillin-tazobactam.
Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Imipenem/farmacologia , Infecções Intra-Abdominais/tratamento farmacológico , Sepse/tratamento farmacológico , Animais , Contagem de Colônia Microbiana , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/microbiologia , Feminino , Injeções Intramusculares , Injeções Intraperitoneais , Infecções Intra-Abdominais/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Sepse/microbiologia , Resultado do Tratamento , beta-Lactamases/metabolismoRESUMO
OBJECTIVES: The aim of this study was to evaluate the impact of qnrA1, qnrB1 and qnrS1 on the in vivo efficacies of ciprofloxacin and levofloxacin in an experimental model of pneumonia caused by Escherichia coli. METHODS: Two isogenic groups of E. coli transformants, based on two ATCC 25922 strains, with or without the GyrA mutation Ser83Leu, and carrying qnrA1, qnrB1 or qnrS1, were used in an experimental pneumonia model. The efficacies of ciprofloxacin (40 mg/kg/day) and levofloxacin (50 and 150 mg/kg/day) were evaluated. RESULTS: For the pneumonia caused by the parental strains lacking qnr genes, both fluoroquinolones significantly (P<0.05) reduced the bacterial lung concentration by >7 log10 cfu/g against E. coli ATCC/pBK and between 5.09 and 6.34 log10 cfu/g against E. coli ATCC-S83L/pBK. The presence of any qnr genes in the strains of both isogenic groups diminished the reduction of bacterial lung concentration with any therapy (P<0.05). Furthermore, all therapeutic schemes reduced the percentage of positive blood cultures in both isogenic groups (P<0.05). Finally, the survival results suggest a higher mortality with the strains expressing qnr genes. CONCLUSIONS: The presence of qnrA1, qnrB1 and qnrS1 in E. coli reduced the efficacy of ciprofloxacin and levofloxacin in a murine pneumonia model.
Assuntos
Antibacterianos/administração & dosagem , Ciprofloxacina/administração & dosagem , Infecções por Escherichia coli/tratamento farmacológico , Proteínas de Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Levofloxacino/administração & dosagem , Pneumonia Bacteriana/tratamento farmacológico , Animais , DNA Girase/genética , Modelos Animais de Doenças , Farmacorresistência Bacteriana , Escherichia coli/genética , Infecções por Escherichia coli/microbiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mutantes/genética , Pneumonia Bacteriana/microbiologia , Resultado do TratamentoRESUMO
Staphylococcus epidermidis is a frequent cause of device-associated infections. In this study, we compared the efficacy of daptomycin versus vancomycin against biofilm-producing methicillin-resistant S. epidermidis (MRSE) strains in a murine model of foreign-body and systemic infection. Two bacteremic biofilm-producing MRSE strains were used (SE284 and SE385). The MIC of daptomycin was 1 mg/liter for both strains, and the MICs of vancomycin were 4 and 2 mg/liter for SE284 and for SE385, respectively. The in vitro bactericidal activities of daptomycin and vancomycin were evaluated by using time-kill curves. The model of foreign-body and systemic infection of neutropenic female C57BL/6 mice was used to ascertain in vivo efficacy. Animals were randomly allocated into three groups (n = 15): without treatment (controls) or treated with daptomycin at 50 mg/kg/day or vancomycin at 440 mg/kg/day. In vitro, daptomycin showed concentration-dependent bactericidal activity, while vancomycin presented time-dependent activity. In the experimental in vivo model, daptomycin and vancomycin decreased liver and catheter bacterial concentrations (P < 0.05) and increased the survival and the number of sterile blood cultures (P < 0.05) using both strains. Daptomycin produced a reduction in the bacterial liver concentration higher than 2.5 log(10) CFU/g compared to vancomycin using both strains, with this difference being significant (P < 0.05) for infection with SE385. For the catheter bacterial concentrations, daptomycin reduced the concentration of SE284 3.0 log(10) CFU/ml more than did vancomycin (P < 0.05). Daptomycin is more effective than vancomycin for the treatment of experimental foreign-body and systemic infections by biofilm-producing methicillin-resistant S. epidermidis.
Assuntos
Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Daptomicina/uso terapêutico , Resistência a Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus epidermidis/efeitos dos fármacos , Vancomicina/uso terapêutico , Animais , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Cateteres de Demora/microbiologia , Contagem de Colônia Microbiana , Daptomicina/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Fígado/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana/normas , Sepse/tratamento farmacológico , Sepse/microbiologia , Sepse/mortalidade , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Staphylococcus epidermidis/crescimento & desenvolvimento , Resultado do Tratamento , Vancomicina/farmacologiaRESUMO
This article provides an analysis of the in vitro effect of qnrA1, qnrB1, and qnrS1 genes, combined with quinolone-resistant Ser83Leu substitutions in GyrA and/or Ser80Arg in ParC, on fluoroquinolone (FQ) resistance in isogenic Escherichia coli strains. The association of Ser83Leu substitution in GyrA, Ser80Arg substitution in ParC, and qnr gene expression increased the MIC of ciprofloxacin to 2 µg/ml. qnr genes present in E. coli that harbored a Ser83Leu substitution in GyrA increased mutant prevention concentration (MPC) values to 8 to 32 µg/ml. qnr gene expression in E. coli may play an important role in selecting for one-step FQ-resistant mutants.
Assuntos
DNA Girase/genética , DNA Topoisomerase IV/genética , Proteínas de Escherichia coli/metabolismo , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Fluoroquinolonas/farmacologia , Ciprofloxacina/farmacologia , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Testes de Sensibilidade Microbiana , MutaçãoAssuntos
Síndrome de Behçet/complicações , Tronco Encefálico/patologia , Meningoencefalite/etiologia , Aciclovir/uso terapêutico , Adulto , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/patologia , Ceftriaxona/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Leucocitose/etiologia , Imageamento por Ressonância Magnética , Masculino , Meningoencefalite/tratamento farmacológico , Meningoencefalite/patologia , Resultado do TratamentoRESUMO
Limited data on relative fitness and virulence of antimicrobial-resistant Acinetobacter baumannii are known. We aimed to study the virulence and fitness cost of ciprofloxacin-resistance in A. baumannii (CipR) compared with the susceptible parental wild-type strain (CipS). Human lung epithelial cells were infected with CipS and CipR for 24 h. Competition fitness was monitored in vitro and in vivo in a murine peritoneal sepsis model. We showed that CipR induced less cell death than CipS and CipR growth was slow when in competition with CipS. Altogether, acquisition of ciprofloxacin resistance confers a biological fitness cost and reduces virulence in A. baumannii.
Assuntos
Acinetobacter baumannii/crescimento & desenvolvimento , Acinetobacter baumannii/metabolismo , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Animais , Anti-Infecciosos/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Transporte Biológico Ativo/fisiologia , Linhagem Celular , Sobrevivência Celular , Células Epiteliais/microbiologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Peritônio/microbiologia , Sepse/microbiologia , VirulênciaRESUMO
The in vitro activity and in vivo efficacy of a new ciprofloxacin derivative (UB-8902) were evaluated. In vitro time-kill curves were performed for ciprofloxacin (CIP), moxifloxacin (MXF) and UB-8902 against CIP-susceptible (Ab58) and CIP-resistant (Ab661 and Ab33) Acinetobacter baumannii strains. UB-8902 showed similar bactericidal activity to CIP and MXF against these strains. In the in vivo experiments in mice, the toxicity of UB-8902, its 50% protective dose (PD(50)) (peritoneal sepsis model), its pharmacokinetic/pharmacodynamic (PK/PD) parameters and its efficacy in a pneumonia model were studied. The maximum tolerated dose of UB-8902 was 512 mg/kg. PD(50) values were 16, 128 and 32 mg/kg for Ab58, Ab661 and Ab33, respectively. Pharmacokinetic parameters of UB-8902 were similar to MXF and were lower than those for CIP, whilst pharmacodynamic parameters were better than CIP. In the pneumonia model, UB-8902 decreased the bacterial lung concentration [4.62 colony-forming units (CFU)/g and 4.15log(10)CFU/g] and positive blood cultures (60% and 62.5%) for Ab58 and Ab33, respectively, compared with the control. In conclusion, UB-8902 presents bactericidal activity against A. baumannii strains resistant to CIP. Moreover, it is effective at reducing mortality in a model of peritoneal sepsis with a dose lower than the toxic one, and it is efficacious in a murine pneumonia model.
Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Anti-Infecciosos/farmacologia , Ciprofloxacina/análogos & derivados , Ciprofloxacina/farmacologia , Pneumonia/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/isolamento & purificação , Animais , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/uso terapêutico , Atividade Bactericida do Sangue , Ciprofloxacina/farmacocinética , Ciprofloxacina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana Múltipla , Feminino , Fluoroquinolonas/farmacologia , Dose Letal Mediana , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Conformação Molecular , Pneumonia/microbiologia , Quinolonas/farmacocinética , Quinolonas/farmacologia , Quinolonas/uso terapêuticoAssuntos
Parotidite/etiologia , Infecções por Serratia , Serratia marcescens , Doença Aguda , Aztreonam/administração & dosagem , Aztreonam/uso terapêutico , Cefotaxima/administração & dosagem , Cefotaxima/uso terapêutico , Cefalosporinas/administração & dosagem , Cefalosporinas/uso terapêutico , Criança , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Monobactamas/administração & dosagem , Monobactamas/uso terapêutico , Parotidite/diagnóstico por imagem , Parotidite/tratamento farmacológico , Infecções por Serratia/tratamento farmacológico , Serratia marcescens/isolamento & purificação , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
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